Heterocyclic compounds as LSD1 inhibitors

ABSTRACT

The present invention is directed to compounds of Formula I which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

FIELD OF THE INVENTION

The present invention is directed to heterocyclic compounds andcompostions thereof which are LSD1 inhibitors useful in the treatment ofdiseases such as cancer.

BACKGROUND OF THE INVENTION

Epigenetic modifications can impact genetic variation but, whendysregulated, can also contribute to the development of various diseases(Portela, A. and M. Esteller, Epigenetic modifications and humandisease. Nat Biotechnol, 2010. 28(10): p. 1057-68; Lund, A. H. and M.van Lohuizen, Epigenetics and cancer. Genes Dev, 2004. 18(19): p.2315-35). Recently, in depth cancer genomics studies have discoveredmany epigenetic regulatory genes are often mutated or their ownexpression is abnormal in a variety of cancers (Dawson, M. A. and T.Kouzarides, Cancer epigenetics: from mechanism to therapy. Cell, 2012.150(1): p. 12-27; Waldmann, T. and R. Schneider, Targeting histonemodifications—epigenetics in cancer. Curr Opin Cell Biol, 2013. 25(2):p. 184-9; Shen, H. and P. W. Laird, Interplay between the cancer genomeand epigenome. Cell, 2013. 153(1): p. 38-55). This implies epigeneticregulators function as cancer drivers or are permissive fortumorigenesis or disease progression. Therefore, deregulated epigeneticregulators are attractive therapeutic targets.

One particular enzyme which is associated with human diseases is lysinespecific demethylase-1 (LSD1), the first discovered histone demethylase(Shi, Y., et al., Histone demethylation mediated by the nuclear amineoxidase homolog LSD1. Cell, 2004. 119(7): p. 941-53). It consists ofthree major domains: the N-terminal SWIRM which functions in nucleosometargeting, the tower domain which is involved in protein-proteininteraction, such as transcriptional co-repressor, co-repressor ofRE1-silencing transcription factor (CoREST), and lastly the C terminalcatalytic domain whose sequence and structure share homology with theflavin adenine dinucleotide (FAD)-dependent monoamine oxidases (i.e.,MAO-A and MAO-B) (Forneris, F., et al., Structural basis of LSD1-CoRESTselectivity in histone H3 recognition. J Biol Chem, 2007. 282(28): p.20070-4; Anand, R. and R. Marmorstein, Structure and mechanism oflysine-specific demethylase enzymes. J Biol Chem, 2007. 282(49): p.35425-9; Stavropoulos, P., G. Blobel, and A. Hoelz, Crystal structureand mechanism of human lysine-specific demethylase-1. Nat Struct MolBiol, 2006. 13(7): p. 626-32; Chen, Y., et al., Crystal structure ofhuman histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad SciUSA, 2006. 103(38): p. 13956-61). LSD1 also shares a fair degree ofhomology with another lysine specific demethylase (LSD2) (Karytinos, A.,et al., A novel mammalian flavin-dependent histone demethylase. J BiolChem, 2009. 284(26): p. 17775-82). Although the biochemical mechanism ofaction is conserved in two isoforms, the substrate specificities arethought to be distinct with relatively small overlap. The enzymaticreactions of LSD1 and LSD2 are dependent on the redox process of FAD andthe requirement of a protonated nitrogen in the methylated lysine isthought to limit the activity of LSD1/2 to mono- and di-methylatedlysines at the position of 4 or 9 of histone 3 (H3K4 or H3K9). Thesemechanisms make LSD1/2 distinct from other histone demethylase families(i.e. Jumonji domain containing family) that can demethylate mono-, di-,and tri-methylated lysines through alpha-ketoglutarate dependentreactions (Kooistra, S. M. and K. Helin, Molecular mechanisms andpotential functions of histone demethylases. Nat Rev Mol Cell Biol,2012. 13(5): p. 297-311; Mosammaparast, N. and Y. Shi, Reversal ofhistone methylation: biochemical and molecular mechanisms of histonedemethylases. Annu Rev Biochem, 2010. 79: p. 155-79).

Methylated histone marks on H3K4 and H3K9 are generally coupled withtranscriptional activation and repression, respectively. As part ofcorepressor complexes (e.g., CoREST), LSD1 has been reported todemethylate H3K4 and repress transcription, whereas LSD1, in nuclearhormone receptor complex (e.g., androgen receptor), may demethylate H3K9to activate gene expression (Metzger, E., et al., LSD1 demethylatesrepressive histone marks to promote androgen-receptor-dependenttranscription. Nature, 2005. 437(7057): p. 436-9; Kahl, P., et al.,Androgen receptor coactivators lysine-specific histone demethylase 1 andfour and a half LIM domain protein 2 predict risk of prostate cancerrecurrence. Cancer Res, 2006. 66(23): p. 11341-7). This suggests thesubstrate specificity of LSD1 can be determined by associated factors,thereby regulating alternative gene expressions in a context dependentmanner. In addition to histone proteins, LSD1 may demethylatenon-histone proteins. These include p53 (Huang, J., et al., p53 isregulated by the lysine demethylase LSD1. Nature, 2007. 449(7158): p.105-8), E2F (Kontaki, H. and I. Talianidis, Lysine methylation regulatesE2F1-induced cell death. Mol Cell, 2010. 39(1): p. 152-60), STAT3 (Yang,J., et al., Reversible methylation of promoter-bound STAT3 byhistone-modifying enzymes. Proc Natl Acad Sci USA, 2010. 107(50): p.21499-504), Tat (Sakane, N., et al., Activation of HIV transcription bythe viral Tat protein requires a demethylation step mediated bylysine-specific demethylase 1 (LSD1/KDM1). PLoS Pathog, 2011. 7(8): p.e1002184), and myosin phosphatase target subunit 1 (MYPT1) (Cho, H. S.,et al., Demethylation of RB regulator MYPT1 by histone demethylase LSD1promotes cell cycle progression in cancer cells. Cancer Res, 2011.71(3): p. 655-60). The lists of non-histone substrates are growing withtechnical advances in functional proteomics studies. These suggestadditional oncogenic roles of LSD1 beyond regulating chromatinremodeling. LSD1 also associates with other epigenetic regulators, suchas DNA methyltransferase 1 (DNMT1) (Wang, J., et al., The lysinedemethylase LSD1 (KDM1) is required for maintenance of global DNAmethylation. Nat Genet, 2009. 41(1): p. 125-9) and histone deacetylases(HDACs) complexes (Hakimi, M. A., et al., A core-BRAF35 complexcontaining histone deacetylase mediates repression of neuronal-specificgenes. Proc Natl Acad Sci USA, 2002. 99(11): p. 7420-5; Lee, M. G., etal., Functional interplay between histone demethylase and deacetylaseenzymes. Mol Cell Biol, 2006. 26(17): p. 6395-402; You, A., et al.,CoREST is an integral component of the CoREST-human histone deacetylasecomplex. Proc Natl Acad Sci USA, 2001. 98(4): p. 1454-8). Theseassociations augment the activities of DNMT or HDACs. LSD1 inhibitorsmay therefore potentiate the effects of HDAC or DNMT inhibitors. Indeed,preclinical studies have shown such potential already (Singh, M. M., etal., Inhibition of LSD1 sensitizes glioblastoma cells to histonedeacetylase inhibitors. Neuro Oncol, 2011. 13(8): p. 894-903; Han, H.,et al., Synergistic re-activation of epigenetically silenced genes bycombinatorial inhibition of DNMTs and LSD1 in cancer cells. PLoS One,2013. 8(9): p. e75136).

LSD1 has been reported to contribute to a variety of biologicalprocesses, including cell proliferation, epithelial-mesenchymaltransition (EMT), and stem cell biology (both embryonic stem cells andcancer stem cells) or self-renewal and cellular transformation ofsomatic cells (Chen, Y., et al., Lysine-specific histone demethylase 1(LSD1): A potential molecular target for tumor therapy. Crit RevEukaryot Gene Expr, 2012. 22(1): p. 53-9; Sun, G., et al., Histonedemethylase LSD1 regulates neural stem cell proliferation. Mol CellBiol, 2010. 30(8): p. 1997-2005; Adamo, A., M. J. Barrero, and J. C.Izpisua Belmonte, LSD1 and pluripotency: a new player in the network.Cell Cycle, 2011. 10(19): p. 3215-6; Adamo, A., et al., LSD1 regulatesthe balance between self-renewal and differentiation in human embryonicstem cells. Nat Cell Biol, 2011. 13(6): p. 652-9). In particular, cancerstem cells or cancer initiating cells have some pluripotent stem cellproperties that contribute to the heterogeneity of cancer cells. Thisfeature may render cancer cells more resistant to conventionaltherapies, such as chemotherapy or radiotherapy, and then developrecurrence after treatment (Clevers, H., The cancer stem cell: premises,promises and challenges. Nat Med, 2011. 17(3): p. 313-9; Beck, B. and C.Blanpain, Unravelling cancer stem cell potential. Nat Rev Cancer, 2013.13(10): p. 727-38). LSD1 was reported to maintain an undifferentiatedtumor initiating or cancer stem cell phenotype in a spectrum of cancers(Zhang, X., et al., Pluripotent Stem Cell Protein Sox2 ConfersSensitivity to LSD1 Inhibition in Cancer Cells. Cell Rep, 2013. 5(2): p.445-57; Wang, J., et al., Novel histone demethylase LSD1 inhibitorsselectively target cancer cells with pluripotent stem cell properties.Cancer Res, 2011. 71(23): p. 7238-49). Acute myeloid leukemias (AMLs)are an example of neoplastic cells that retain some of their lessdifferentiated stem cell like phenotype or leukemia stem cell (LSC)potential. Analysis of AML cells including gene expression arrays andchromatin immunoprecipitation with next generation sequencing (ChIP-Seq)revealed that LSD1 may regulate a subset of genes involved in multipleoncogenic programs to maintain LSC (Harris, W. J., et al., The histonedemethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemiastem cells. Cancer Cell, 2012. 21(4): p. 473-87; Schenk, T., et al.,Inhibition of the LSD1 (KDM1A) demethylase reactivates theall-trans-retinoic acid differentiation pathway in acute myeloidleukemia. Nat Med, 2012. 18(4): p. 605-11). These findings suggestpotential therapeutic benefit of LSD1 inhibitors targeting cancershaving stem cell properties, such as AMLs.

Overexpression of LSD1 is frequently observed in many types of cancers,including bladder cancer, NSCLC, breast carcinomas, ovary cancer,glioma, colorectal cancer, sarcoma including chondrosarcoma, Ewing'ssarcoma, osteosarcoma, and rhabdomyosarcoma, neuroblastoma, prostatecancer, esophageal squamous cell carcinoma, and papillary thyroidcarcinoma. Notably, studies found over-expression of LSD1 wassignificantly associated with clinically aggressive cancers, forexample, recurrent prostate cancer, NSCLC, glioma, breast, colon cancer,ovary cancer, esophageal squamous cell carcinoma, and neuroblastoma. Inthese studies, either knockdown of LSD1 expression or treatment withsmall molecular inhibitors of LSD1 resulted in decreased cancer cellproliferation and/or induction of apoptosis. See, e.g., Hayami, S., etal., Overexpression of LSD1 contributes to human carcinogenesis throughchromatin regulation in various cancers. Int J Cancer, 2011. 128(3): p.574-86; Lv, T., et al., Over-expression of LSD1 promotes proliferation,migration and invasion in non-small cell lung cancer. PLoS One, 2012.7(4): p. e35065; Serce, N., et al., Elevated expression of LSD1(Lysine-specific demethylase 1) during tumour progression frompre-invasive to invasive ductal carcinoma of the breast. BMC ClinPathol, 2012. 12: p. 13; Lim, S., et al., Lysine-specific demethylase 1(LSD1) is highly expressed in ER-negative breast cancers and a biomarkerpredicting aggressive biology. Carcinogenesis, 2010. 31(3): p. 512-20;Konovalov, S. and I. Garcia-Bassets, Analysis of the levels oflysine-specific demethylase 1 (LSD1) mRNA in human ovarian tumors andthe effects of chemical LSD1 inhibitors in ovarian cancer cell lines. JOvarian Res, 2013. 6(1): p. 75; Sareddy, G. R., et al., KDM1 is a noveltherapeutic target for the treatment of gliomas. Oncotarget, 2013. 4(1):p. 18-28; Ding, J., et al., LSD1-mediated epigenetic modificationcontributes to proliferation and metastasis of colon cancer. Br JCancer, 2013. 109(4): p. 994-1003; Bennani-Baiti, I. M., et al.,Lysine-specific demethylase 1 (LSD1/KDM1A/AOF2/BHC110) is expressed andis an epigenetic drug target in chondrosarcoma, Ewing's sarcoma,osteosarcoma, and rhabdomyosarcoma. Hum Pathol, 2012. 43(8): p. 1300-7;Schulte, J. H., et al., Lysine-specific demethylase 1 is stronglyexpressed in poorly differentiated neuroblastoma: implications fortherapy. Cancer Res, 2009. 69(5): p. 2065-71; Crea, F., et al., Theemerging role of histone lysine demethylases in prostate cancer. MolCancer, 2012. 11: p. 52; Suikki, H. E., et al., Genetic alterations andchanges in expression of histone demethylases in prostate cancer.Prostate, 2010. 70(8): p. 889-98; Yu, Y., et al., High expression oflysine-specific demethylase 1 correlates with poor prognosis of patientswith esophageal squamous cell carcinoma. Biochem Biophys Res Commun,2013. 437(2): p. 192-8; Kong, L., et al., Immunohistochemical expressionof RBP2 and LSD1 in papillary thyroid carcinoma. Rom J Morphol Embryol,2013. 54(3): p. 499-503.

Recently, the induction of CD86 expression by inhibiting LSD1 activitywas reported (Lynch, J. T., et al., CD86 expression as a surrogatecellular biomarker for pharmacological inhibition of the histonedemethylase lysine-specific demethylase 1. Anal Biochem, 2013. 442(1):p. 104-6). CD86 expression is a marker of maturation of dendritic cells(DCs) which are involved in antitumor immune response. Notably, CD86functions as a co-stimulatory factor to activate T cell proliferation(Greaves, P. and J. G. Gribben, The role of B7 family molecules inhematologic malignancy. Blood, 2013. 121(5): p. 734-44; Chen, L. and D.B. Flies, Molecular mechanisms of T cell co-stimulation andco-inhibition. Nat Rev Immunol, 2013. 13(4): p. 227-42).

In addition to playing a role in cancer, LSD1 activity has also beenassociated with viral pathogenesis. Particularly, LSD1 activity appearsto be linked with viral replications and expressions of viral genes. Forexample, LSD1 functions as a co-activator to induce gene expression fromthe viral immediate early genes of various type of herpes virusincluding herpes simplex virus (HSV), varicella zoster virus (VZV), andβ-herpesvirus human cytomegalovirus (Liang, Y., et al., Targeting theJMJD2 histone demethylases to epigenetically control herpesvirusinfection and reactivation from latency. Sci Transl Med, 2013. 5(167):p. 167ra5; Liang, Y., et al., Inhibition of the histone demethylase LSD1blocks alpha-herpesvirus lytic replication and reactivation fromlatency. Nat Med, 2009. 15(11): p. 1312-7). In this setting, a LSD1inhibitor showed antiviral activity by blocking viral replication andaltering virus associated gene expression.

Recent studies have also shown that the inhibition of LSD1 by eithergenetic depletion or pharmacological intervention increased fetal globingene expression in erythroid cells (Shi, L., et al., Lysine-specificdemethylase 1 is a therapeutic target for fetal hemoglobin induction.Nat Med, 2013. 19(3): p. 291-4; Xu, J., et al., Corepressor-dependentsilencing of fetal hemoglobin expression by BCL11A. Proc Natl Acad SciUSA, 2013. 110(16): p. 6518-23). Inducing fetal globin gene would bepotentially therapeutically beneficial for the disease ofβ-globinopathies, including β-thalassemia and sickle cell disease wherethe production of normal β-globin, a component of adult hemoglobin, isimpaired (Sankaran, V. G. and S. H. Orkin, The switch from fetal toadult hemoglobin. Cold Spring Harb Perspect Med, 2013. 3(1): p. a011643;Bauer, D. E., S. C. Kamran, and S. H. Orkin, Reawakening fetalhemoglobin: prospects for new therapies for the beta-globin disorders.Blood, 2012. 120(15): p. 2945-53). Moreover, LSD1 inhibition maypotentiate other clinically used therapies, such as hydroxyurea orazacitidine. These agents may act, at least in part, by increasingγ-globin gene expression through different mechanisms.

In summary, LSD1 contributes to tumor development by altering epigeneticmarks on histones and non-histone proteins. Accumulating data havevalidated that either genetic depletion or pharmacological interventionof LSD1 normalizes altered gene expressions, thereby inducingdifferentiation programs into mature cell types, decreasing cellproliferation, and promoting apoptosis in cancer cells. Therefore, LSD1inhibitors alone or in combination with established therapeutic drugswould be effective to treat the diseases associated with LSD1 activity.

SUMMARY OF THE INVENTION

The present invention is directed to, inter alia, a compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound of Formula I and at least onepharmaceutically acceptable carrier.

The present invention is further directed to a method of inhibiting LSD1comprising contacting the LSD1 with a compound of Formula I.

The present invention is further directed to a method of modulating LSD1comprising contacting the LSD1 with a compound of Formula I. The presentinvention is further directed to a method of mediating LSD1 comprisingcontacting the LSD1 with a compound of Formula I. The present inventionis further directed to a method of modulating LSD1 signaling comprisingcontacting the LSD1 with a compound of Formula I.

The present invention is further directed to a method of treating anLSD1-mediated disease in a patient comprising administering to thepatient a therapeutically effective amount of a compound of Formula I.

DETAILED DESCRIPTION

The present invention provides, inter alia, LSD1-inhibiting compoundssuch as a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, or4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or4-10 membered heterocycloalkyl of ring A each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsselected from N, O, and S, wherein N or S is optionally oxidized; andwherein a ring-forming carbon atom of the C₃₋₁₀ cycloalkyl or 4-10membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group;

X is N or CR^(X), wherein R^(X) is H, OH, CN, halo, NH₂, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NHC₁₋₄ alkyl, N(C₁₋₄alkyl)₂ or C₁₋₄ alkylthio;

U is N or CR^(U), wherein R^(U) is H, OH, CN, halo, NH₂, C₁₋₄ alkyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NHC₁₋₄ alkyl, N(C₁₋₄alkyl)₂ or C₁₋₄ alkylthio;

Y is N or CR⁴;

Z is N or CR⁵;

with the proviso that at least one of U, Y, and Z is N;

R¹ is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆haloalkoxy, NHOH, NHOC₁₋₆ alkyl, Cy¹, CN, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1) NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1) NR^(c1)S(O)R^(b1) NR^(c1)S(O)₂R^(b1)NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1), -L¹-R⁶, or -L²-NR⁷R⁸; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, or3 substituents independently selected from Cy¹, halo, CN, OH, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);

L¹ is a bond, —O—, —NR⁹—, —C(O)NH—, —NHC(O)—, C₁₋₄ alkylene; wherein R⁹is H, C₁₋₆ alkyl, —C(O)C₁₋₆ alkyl or —C(O)OC₁₋₆ alkyl;

L² is a bond, —C(O)—, C₁₋₄ alkylene, —O—C₁₋₄ alkylene-, —C₁₋₄alkylene-O—, —C₁₋₄ alkylene-NR⁹—, or —NR⁹—C₁₋₄ alkylene-;

R³, at each occurrence, is independently selected from H, OH, CN, halo,NH₂, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NHC₁₋₄alkyl, N(C₁₋₄ alkyl)₂, and C₁₋₄ alkylthio;

R³, at each occurrence, is independently selected from H, Cy², halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2) NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2) NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from Cy², halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2) NR^(c2)C(O)R^(b2) NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2);

or two adjacent R³ substituents on ring A taken together with the atomsto which they are attached form a fused 5- or 6-memberedheterocycloalkyl ring, a fused C₃₋₆ cycloalkyl ring, or a fused 5- or6-membered heteroaryl ring, each of which is optionally substituted with1 or 2 independently selected R^(A) substituents, wherein a ring carbonof the fused 5- or 6-membered heterocycloalkyl ring or fused C₃₋₆cycloalkyl ring is optionally replaced by a carbonyl group;

alternatively, two R^(A) substituents attached to the same carbon of thefused 5- or 6-membered heterocycloalkyl ring or fused C₃₋₆ cycloalkylring taken together form a C₃₋₆ cycloalkyl ring or 4- to 7-memberedheterocycloalkyl ring;

R⁴ and R⁵ are each independently selected from H, Cy³, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, CN, OR^(a3), SR^(a3),C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3) S(O)₂R^(b3), NR^(c3) S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromCy³, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3)NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),C(═NR^(e3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3);

R⁶ is 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl-C₁₋₄alkyl, 4- to 10-membered heterocycloalkyl, or 4- to 10-memberedheterocycloalkyl-C₁₋₄ alkyl, each of which is optionally substitutedwith 1, 2, 3 or 4 independently selected R^(A) substituents;

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform 4- to 10-membered heterocycloalkyl ring having 0, 1 or 2heteroatoms selected from N and S in addition to the nitrogen atomconnected to R⁷ and R⁸, wherein a ring-forming carbon atom of theheterocycloalkyl group is optionally substituted by an oxo group, andwherein the heterocycloalkyl is optionally substituted with 1, 2, 3 or 4independently selected R^(B) substituents;

each R^(A) is independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, Cy², C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4),C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, Cy³, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, and 4-10membered heterocycloalkyl-C₁₋₄ alkyl are each optionally substituted by1, 2, or 3 substituents independently selected from halo, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)C(O)NR^(c4)R^(d4), C(═NR^(e4))R^(b4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4);

each R^(B) is independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, Cy³, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl, 4-10membered heterocycloalkyl-C₁₋₄ alkyl, CN, NO₂, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, Cy⁴, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl, 5-10 membered heteroaryl-C₁₋₄ alkyl and 4-10membered heterocycloalkyl-C₁₋₄ alkyl are each optionally substituted by1, 2, or 3 substituents independently selected from halo, C₁₋₆haloalkyl, CN, NO₂, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5),C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5),C(═NR^(e5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

each Cy¹, Cy², Cy³, and Cy⁴ is independently selected from C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-membered heteroaryl, and 4-10 memberedheterocycloalkyl, each of which is optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(Cy);

each R^(Cy) is independently selected from H, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ cyanoalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,phenyl-C₁₋₄ alkyl-, C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-7 membered heterocycloalkyl)-C₁₋₄alkyl-, oxo, CN, NO₂, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), OC(O)R^(b4), OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4), wherein saidC₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, phenyl, C₃₋₇ cycloalkyl, 5-6membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C₁₋₄ alkyl-,C₃₋₇ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, and(4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted by 1, 2, or 3 substituents independently selected from C₁₋₆alkyl, C₁₋₄ haloalkyl, C₁₋₆ cyanoalkyl, halo, CN, NO₂, OR^(a4), SR^(a4),C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4), OC(O)R^(b4),OC(O)NR^(c4)R^(d4), C(═NR^(e4))NR^(c4)R^(d4),NR^(c4)C(═NR^(e4))NR^(c4)R^(d4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)C(O)NR^(c4)R^(d4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);

each R^(a1), R^(b1), R^(c1), and R^(d1) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

or any R^(c1) and R^(d1) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl,halo CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,C₆₋₁₀ aryl, and 5-6 membered heteroaryl are each optionally substitutedby 1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5) NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

each R^(a2), R^(b2), R^(c2), and R^(d2) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

or any R^(c2) and R^(d2) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl, halo,CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl are each optionally substituted by1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5) NR^(c5)C(O)R^(b5) NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

each R^(a3), R^(b3), R^(c3), and R^(d3) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

or any R^(c3) and R^(d3) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, C₁₋₆ haloalkyl, halo,CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5),wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl are each optionally substituted by1, 2, or 3 substituents independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

each R^(a4), R^(b4), R^(c4), and R^(d4) is independently selected fromH, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, whereinsaid C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, halo, CN, OR^(a5),SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5) NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5),and S(O)₂NR^(c5)R^(d5);

or any R^(c4) and R^(d4) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl groupoptionally substituted with 1, 2, or 3 substituents independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5),OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))NR^(c5)R^(d5),NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)R^(b5), S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);

each R^(a5), R^(b5), R^(c5), and R^(d5) is independently selected fromH, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, whereinsaid C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,CN, amino, halo, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy;

each R^(e1), R^(e2), R^(e3), R^(e4), and R^(e5) is independentlyselected from H, C₁₋₄ alkyl, and CN;

the subscript m is 1 or 2; and

the subscript n is 1, 2, 3 or 4.

In some embodiments, the compounds of the invention have Formula II:

In some embodiments, the compounds of the invention have Formula III:

In some embodiments, U is CR^(U).

In some embodiments, the compounds of the invention have Formula IIIb:

In some embodiments, U is N.

In some embodiments, the compounds of the invention have Formula IIIa:

In some embodiments, Y is N.

In some embodiments, Y is CR⁴.

In some embodiments, Z is N.

In some embodiments, Z is CR⁵.

In some embodiments, Y and Z are each CH.

In some embodiments, (i) U, Y and Z are each N; (ii) U and Z are N and Yis CR⁴; (iii) U and Y are N and Z is CR⁵; (iv) U is N, Y is CR⁴, and Zis CR⁵; (v) U is CR^(U) and both Y and Z are N; (vi) U is CR^(U), Y isN, and Z is CR⁵; or (vii) U is CR^(U), Y is CR⁴, and Z is N.

In some embodiments, U, Y and Z are each N.

In some embodiments, U and Z are N and Y is CR⁴.

In some embodiments, U and Y are N and Z is CR⁵.

In some embodiments, U is N, Y is CR⁴, and Z is CR⁵.

In some embodiments, U is CR^(U) and both Y and Z are N.

In some embodiments, U is CR^(U), Y is N, and Z is CR⁵.

In some embodiments, U is CR^(U), Y is CR⁴, and Z is N.

In some embodiments, two of U, Y, and Z are N.

In some embodiments, one of U, Y, and Z are N.

In some embodiments, ring A is C₆₋₁₀ aryl, 5-10 membered heteroaryl, or4-10 membered heterocycloalkyl, wherein the 5-10 membered heteroaryl or4-10 membered heterocycloalkyl of ring A each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsselected from N, O, and S, wherein N or S is optionally oxidized; andwherein a ring-forming carbon atom of the 4-10 membered heterocycloalkylis optionally substituted by oxo to form a carbonyl group.

In some embodiments, ring A is phenyl, 5-6 membered heteroaryl, or 4-7membered heterocycloalkyl, wherein the 5-6 membered heteroaryl or 4-7membered heterocycloalkyl of ring A each has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms selected from N,O, and S, wherein N or S is optionally oxidized; and wherein aring-forming carbon atom of the 4-10 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group.

In some embodiments, ring A is C₆₋₁₀ aryl.

In some embodiments, ring A is phenyl.

In some embodiments, ring A is 5-10 membered heteroaryl. In someembodiments, ring A is 5-6 membered heteroaryl. In some embodiments,ring A is 6 membered heteroaryl. In some embodiments, ring A is 5membered heteroaryl.

In some embodiments, ring A is pyridyl, 1H-indazolyl,1H-pyrrolo[2,3-b]pyridinyl, or 1H-benzo[d]imidazolyl.

In some embodiments, ring A is pyridyl.

In some embodiments, ring A is 4-10 membered heterocycloalkyl having atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms selected from N, O, and S, wherein N or S is optionallyoxidized, and wherein a ring-forming carbon atom is optionallysubstituted by oxo to form a carbonyl group.

In some embodiments, ring A is 4-7 membered heterocycloalkyl having atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms selected from N, O, and S, wherein N or S optionallyoxidized, and wherein a ring-forming carbon atom is optionallysubstituted by oxo to form a carbonyl group.

In some embodiments, ring A is 2-oxo-2,3-dihydro-1H-indolyl;2-oxo-2,3-dihydro-1,3-benzoxazolyl;3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl;3-oxo-3,4-dihydro-2H-1,4-benzoxazinyl; 1H-pyrazolo[3,4-b]pyridinyl;3-methyl-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl;2-oxo-2,3-dihydro-1H-benzimidazolyl; 1H-benzimidazolyl;2-oxo-2,3-dihydro[1,3]oxazolo[4, 5-b]pyridinyl, or2,3-dihydro-1-benzofuranyl.

In some embodiments, ring A is 2,3-dihydro-1H-indolyl;2,3-dihydro-1,3-benzoxazolyl; 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl;3,4-dihydro-2H-1,4-benzoxazinyl; or 2,3-dihydro-1-benzofuran.

In some embodiments, ring A is 2-oxo-2,3-dihydro-1H-indolyl;2-oxo-2,3-dihydro-1,3-benzoxazolyl;3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl;3-oxo-3,4-dihydro-2H-1,4-benzoxazinyl; or 2,3-dihydro-1-benzofuran.

In some embodiments, ring A is phenyl; 2,3-dihydro-1,4-benzodioxine;2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl;5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl;2-oxo-1,2,3,4-tetrahydroquinolin-7-yl; pyridyl;2-oxo-2,3-dihydro-1,3-benzoxazolyl; 1,3-benzothiazol-5-yl; 2,3-dihydro-1H-inden-5-yl; 1H-pyrrolo[2,3-b]pyridinyl; 8-quinoxalin-6-yl;2-oxo-1,2,3,4-tetrahydroquinolin-6-yl; or 1H-pyrazolo[3,4-b]pyridinyl.

In some embodiments, ring A is phenyl; pyridyl; 1H-indazolyl;1H-pyrrolo[2,3-b]pyridinyl; 1H-benzo[d]imidazolyl;2-oxo-2,3-dihydro-1H-indolyl; 2-oxo-2,3-dihydro-1,3-benzoxazolyl;3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl;3-oxo-3,4-dihydro-2H-1,4-benzoxazinyl; 1H-pyrazolo[3,4-b]pyridinyl;3-methyl-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl;2-oxo-2,3-dihydro-1H-benzimidazolyl; 1H-benzimidazolyl;2-oxo-2,3-dihydro[1,3]oxazolo[4,5-b]pyridinyl;2,3-dihydro-1-benzofuranyl; 2,3-dihydro-1H-indolyl;2,3-dihydro-1,3-benzoxazolyl; 3,4-dihydro-2H-1,4-benzoxazinyl;2,3-dihydro-1,4-benzodioxine; 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl;5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl;2-oxo-1,2,3,4-tetrahydroquinolin-7-yl; 1,3-benzothiazol-5-yl;2,3-dihydro-1H-inden-5-yl; 8-quinoxalin-6-yl; or2-oxo-1,2,3,4-tetrahydroquinolin-6-yl.

In some embodiments, R³, at each occurrence, is independently selectedfrom Cy², C₁₋₆ alkyl, CN, OR^(a2), C(O)NR^(c2)R^(d2), and NR^(c2)R^(d2);wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or 3substituents independently selected from Cy², C(O)R^(b2), andC(O)NR^(c2)R^(d2).

In some embodiments, R³ is, at each occurrence, CN, methyl, methoxy,1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, —C(O)N(CH₃)₂, dimethylamino,4-methylpiperazinylmethyl, morpholinyl,4-methylpiperazinylcarbonylmethyl, morpholinylmethyl, morpholinoethyl,or 3-cyano-1-pyrrolidinylmethyl.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form a fused 5- or6-membered heterocycloalkyl ring, a fused C₃₋₆ cycloalkyl ring, or afused 5- or 6-membered heteroaryl ring, each of which is optionallysubstituted with 1 or 2 independently selected R^(A) substituents;wherein a ring carbon of the fused 5- or 6-membered heterocycloalkylring or fused C₃₋₆ cycloalkyl ring is optionally replaced by a carbonylgroup;

-   -   alternatively, two R^(A) substituents attached to the same        carbon of the fused 5- or 6-membered heterocycloalkyl or fused        C₃₋₆ cycloalkyl taken together form a C₃₋₆ cycloalkyl or 4- to        7-membered heterocycloalkyl ring.

In some embodiments, two R^(A) substituents attached to the same carbonof the fused 5- or 6-membered heterocycloalkyl or fused C₃₋₆ cycloalkyltaken together form a cyclopropyl group.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form a fused ringselected from 1-methylpyrrolidine, 4-methyl-3-oxo-morpholine,1-methylimidazole, 1-methylpiperidine, 1-methyl-2-oxopyrrolidine, and1-methylpyrazole, each of which is optionally substituted with 1 or 2R^(A) substituents.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form a fused ringselected from pyrrolidine, 3-oxo-morpholine, imidazole, piperidine,2-oxopyrrolidine, and pyrazole, each of which is optionally substitutedwith 1 or 2 R^(A) substituents.

In some embodiments, R³ is C₁₋₆ alkyl, halo, C₁₋₆ hydroxyalkyl, C₁₋₆haloalkyl, CN, OR^(a2), 1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl,NR^(c2)C(O)OR^(a2), —(C₁₋₆ alkyl)-NR^(c2)C(O)OR^(a2), C(O)NR^(c2)R^(d2),NR^(c2)R^(d2), piperazinylmethyl, 4-methylpiperazinylmethyl,piperidinyl, morpholinyl, 4-methylpiperazinylcarbonylmethyl,morpholinylmethyl, or 3-cyano-1-pyrrolidinyl.

In some embodiments, R³ is C₁₋₆ alkyl, CN, OR^(a2), 1-pyrrolidinyl,2-oxo-1-pyrrolidinyl, C(O)NR^(c2)R^(d2), NR^(c2)R^(d2),piperazinylmethyl, 4-methylpiperazinylmethyl, piperidinyl, morpholinyl,4-methylpiperazinylcarbonylmethyl, morpholinylmethyl or3-cyano-1-pyrrolidinyl.

In some embodiments, R³ is CN, F, hydroxymethyl, (CH₃O)C(O)N(CH₃)—,(CH₃O)C(O)N(CH₃)-methyl, difluoromethyl, amino, methyl, methoxy,1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, —C(O)N(CH₃)₂, dimethylamino,4-methylpiperazinylmethyl, morpholinyl,4-methylpiperazinylcarbonylmethyl, morpholinylmethyl, morpholinoethyl,or 3-cyano-1-pyrrolidinylmethyl.

In some embodiments, R³ is, at each occurrence, CN, F, hydroxymethyl,(CH₃O)C(O)N(CH₃)—, (CH₃O)C(O)N(CH₃)-methyl, difluoromethyl, methyl,methoxy, —C(O)N(CH₃)₂, dimethylamino, morpholinylmethyl,(CH₃)S(O₂)N(CH₃)-methyl, (CH₃)₂NC(O)N(CH₃)-methyl, Cl, 1-hydroxyethyl,methoxymethyl, isopropyl, ethyl, (CH₃)S(O₂)N(CH₃)—, or ethoxy.

In some embodiments, R³ is CN, F, hydroxymethyl, (CH₃O)C(O)N(CH₃)—,(CH₃O)C(O)N(CH₃)-methyl, difluoromethyl, amino, methyl, methoxy,1-pyrrolidinyl, 2-oxo-1-pyrrolidinyl, —C(O)N(CH₃)₂, dimethylamino,4-methylpiperazinylmethyl, morpholinyl,4-methylpiperazinylcarbonylmethyl, morpholinylmethyl, morpholinoethyl,or 3-cyano-1-pyrrolidinylmethyl, (CH₃)S(O₂)N(CH₃)-methyl,(CH₃)₂NC(O)N(CH₃)-methyl, Cl, 1-hydroxyethyl, methoxymethyl, isopropyl,ethyl, (CH₃)S(O₂)N(CH₃)—, or ethoxy.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form fused 5- or6-membered heterocycloalkyl, fused C₃₋₆ cycloalkyl or fused 5- or6-membered heteroaryl, each of which is optionally substituted with 1-2independently selected R^(A) substituents, wherein a ring carbon of thefused 5- or 6-membered heterocycloalkyl or fused C₃₋₆ cycloalkyl isoptionally replaced by a carbonyl group.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form fused 5- or6-membered heterocycloalkyl, which is optionally substituted with 1-2independently selected R^(A) substituents, wherein a ring carbon of thefused 5- or 6-membered heterocycloalkyl is optionally replaced by acarbonyl group.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form a fused2,3-dihydro-1H-pyrrolyl; 2-oxo-2,3-dihydro-1H-pyrrolyl;2,3-dihydro-oxazolyl; 2-oxo-2,3-dihydro-oxazolyl;3,4-dihydro-2H-1,4-oxazinyl; 3-oxo-3,4-dihydro-2H-1,4-oxazinyl; or2,3-dihydro-furanyl group, each of which is optionally substituted with1-2 independently selected R^(A) substituents.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form a fused2,3-dihydro-1H-pyrrolyl group, which is optionally substituted with oneR^(A) substituent.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form a2-oxo-2,3-dihydro-1H-pyrrolyl group, which is optionally substitutedwith one R^(A) substituent.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form a fused2,3-dihydro-oxazolyl group, which is optionally substituted with oneR^(A) substituent.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form a fused2-oxo-2,3-dihydro-oxazolyl group, which is optionally substituted withone R^(A) substituent.

In some embodiments, two adjacent R³ substituents on ring A takentogether with the atoms to which they are attached form a fused2,3-dihydro-furanyl group, which is optionally substituted with oneR^(A) substituent.

In some embodiments, R^(A) is C₁₋₄ alkyl.

In some embodiments, R^(A) is methyl.

In some embodiments, R^(A) is —C(O)NR^(c4)R^(d4), wherein R^(c4) andR^(d4) are each, independently selected from H and C₁₋₄ alkyl.

In some embodiments, R^(A) is —C(O)N(CH₃)₂.

In some embodiments, R¹ is -L¹-R⁶ or -L²-NR⁷R⁸.

In some embodiments, R¹ is -L²-NR⁷R⁸, wherein L² is a bond, —C(O)—, C₁₋₄alkylene, —O—C₁₋₄ alkylene, —C₁₋₄ alkylene-O—, C₁₋₄ alkylene-NH— or—NH—C₁₋₄ alkylene.

In some embodiments, L² is a —O—C₁₋₄ alkylene.

In some embodiments, R⁷ and R⁸ together with the nitrogen atom to whichthey are attached form 4- to 6-membered heterocycloalkyl ring having 0,1 or 2 heteroatoms selected from N and S in addition to the nitrogenatom connected to R⁷ and R⁸, wherein a ring-forming carbon atom of theheterocycloalkyl group is optionally substituted by an oxo group, andwherein the heterocycloalkyl is optionally substituted with 1, 2, 3 or 4independently selected R^(B) substituents.

In some embodiments, R¹ is -L¹-R⁶.

In some embodiments, L¹ is —O—.

In some embodiments, R⁶ is 5- to 10-membered heteroaryl-C₁₋₄ alkyl or 4-to 10-membered heterocycloalkyl-C₁₋₄ alkyl, each of which is optionallysubstituted with 1, 2, 3 or 4 independently selected R^(A) substituents.

In some embodiments, R⁶ is 4- to 10-membered heterocycloalkyl-C₁₋₄ alkylwhich is optionally substituted with 1, 2, 3 or 4 independently selectedR^(A) substituents.

In some embodiments, R⁶ is pyrrolidinyl-C₁₋₄ alkyl- which is optionallysubstituted with 1, 2 or 3 independently selected R^(A) substituents. Insome embodiments, R⁶ is pyrrolidinyl-methylene-which is optionallysubstituted with 1, 2 or 3 independently selected R^(A) substituents.

In some embodiments, R⁶ is piperidinyl-C₁₋₄ alkyl- which is optionallysubstituted with 1, 2 or 3 independently selected R^(A) substituents. Insome embodiments, R⁶ is piperidinyl-methylene-which is optionallysubstituted with 1, 2 or 3 independently selected R^(A) substituents.

In some embodiments, R¹ is OR^(a1).

In some embodiments, R¹ is OR^(a1), wherein R^(a1) is C₁₋₆ alkylsubstituted with Cy⁴.

In some embodiments, R¹ is OR^(a1), wherein R^(a1) is methylenesubstituted with Cy⁴.

In some embodiments, R¹ is OR^(a1), wherein R^(a1) is methylenesubstituted with 4-10 membered heterocycloalkyl optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(Cy).

In some embodiments, R¹ is OR^(a1), wherein R^(a1) is methylenesubstituted with 4-7 membered heterocycloalkyl optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(Cy).

In some embodiments, Cy⁴ is pyrrolidinyl or piperidinyl optionallysubstituted with 1 or 2 substituents independently selected from R^(Cy).

In some embodiments, R¹ is (1-methylpiperidin-3-yl)methoxy,(1-ethylpiperidin-3-yl)methoxy, (2-cyanoethylpiperidin-3-yl)methoxy,(2-hydroxyethylpiperidin-3-yl)methoxy,(2-methoxyethylpiperidin-3-yl)methoxy, 4-dimethylaminopiperidin-1-yl,3-dimethylaminopyrrolidin-1-yl, 7-methyl-2,7-diazaspiro[4.4]non-2-yl, or(1-methylpyrrolidin-3-yl)methoxy.

In some embodiments, R¹ is (1-methylpiperidin-3-yl)methoxy or(1-methylpyrrolidin-3-yl)methoxy.

In some embodiments, R¹ is (1-methylpiperidin-3-yl)methoxy,(1-ethylpiperidin-3-yl)methoxy, (2-cyanoethylpiperidin-3-yl)methoxy,4-dimethylaminopiperidin-1-yl, 3-dimethylaminopyrrolidin-1-yl,(2-hydroxypropylpiperidin-3-yl)methoxy, or2-hydroxy-2-methylpropyl)piperidin-3-yl]methoxy.

In some embodiments, R¹ is (1-methylpiperidin-3-yl)methoxy,(1-ethylpiperidin-3-yl)methoxy, (2-cyanoethylpiperidin-3-yl)methoxy,(2-hydroxyethylpiperidin-3-yl)methoxy,(2-methoxyethylpiperidin-3-yl)methoxy, 4-dimethylaminopiperidin-1-yl,3-dimethylaminopyrrolidin-1-yl, 7-methyl-2,7-diazaspiro[4.4]non-2-yl,(1-methylpyrrolidin-3-yl)methoxy, or2-hydroxy-2-methylpropyl)piperidin-3-yl]methoxy.

In some embodiments, R² is H.

In some embodiments, R⁴ is H.

In some embodiments, R⁵ is H.

In some embodiments, R^(U) is H.

In some embodiments, R^(X) is H.

In some embodiments, m is 1.

In some embodiments, n is 1.

In some embodiments, the compounds of the invention have Formula IVa,IVb, IVc, IVd, IVe, or IVf:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds provided herein have Formula IVg,IVh, or IVi:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of the invention have Formula IVa orIVb:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of the invention have Formula IVa.

In some embodiments, the compounds of the invention have Formula IVb.

In some embodiments, the compounds of the invention have Formula IVc.

In some embodiments, the compounds of the invention have Formula IVd.

In some embodiments, the compounds of the invention have Formula IVe.

In some embodiments, the compounds of the invention have Formula IVf.

In some embodiments, the compounds of the invention have Formula IVg.

In some embodiments, the compounds of the invention have Formula IVh.

In some embodiments, the compounds of the invention have Formula IVi.

In some embodiments of compounds of Formula I, the present disclosureprovides compounds having Formula V:

wherein X¹ is CH or N.

In some embodiments of the compounds of Formula V:

two R³ substituents taken together with the carbon atoms to which theyare attached form a fused 5-membered heterocycloalkyl ring or a fused5-membered heteroaryl ring, each of which is optionally substituted with1 or 2 independently selected R^(A) substituents, wherein a ring carbonof the fused 5-membered heterocycloalkyl ring is optionally replaced bya carbonyl group;

X is N or CH;

L² is a bond or O—C₁₋₄ alkylene; and

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform 4- to 7-membered heterocycloalkyl ring having 0, 1 or 2 heteroatomsselected from N and S in addition to the nitrogen atom connected to R⁷and R⁸, wherein the heterocycloalkyl is optionally substituted with 1,2, 3 or 4 independently selected R^(B) substituents.

In some aspects of these embodiments, X¹ is CH. In other aspects ofthese embodiments X¹ is N. In some aspects of these embodiments, L² is abond, —C(O)—, C₁₋₄ alkylene, —O—C₁₋₄ alkylene-, —C₁₋₄ alkylene-O—, —C₁₋₄alkylene-NR⁹—, or —NR⁹—C₁₋₄alkylene-. In some aspects of theseembodiments, two R³ substituents taken together with the carbon atoms towhich they are attached form a fused 5-membered heterocycloalkyl ring ora fused 5-membered heteroaryl, each of which is optionally substitutedwith 1 or 2 independently selected R^(A) substituents, wherein a ringcarbon of the fused 5-membered heterocycloalkyl ring is optionallyreplaced by a carbonyl group. In some instances, a ring carbon of thefused 5-membered heterocycloalkyl ring is replaced by a carbonyl group.In some instances, R^(A) is C₁₋₄ alkyl such as methyl. In someinstances, the fused 5-membered heterocycloalkyl ring or fused5-membered heteroaryl has 1 or 2 heteroatoms as ring members selectedfrom O, N or S. In some aspects of these embodiments, R⁷ and R⁸ togetherwith the nitrogen atom to which they are attached form 4- to 7-memberedheterocycloalkyl ring having 0, 1 or 2 additional heteroatoms selectedfrom N and S as ring members, wherein a ring-forming carbon atom of theheterocycloalkyl group is optionally substituted by an oxo group, andwherein the heterocycloalkyl is optionally substituted with 1, 2, 3 or 4independently selected R^(B) substituents. In some instances, R^(B) isC₁₋₄ alkyl such as methyl.

In one embodiment of compounds of Formula V, L² is a bond. In anotherembodiment of compounds of Formula V, L² is —O—C₁₋₄ alkylene-. In yetanother embodiment of compounds of Formula V, L² is —OCH₂—.

In some embodiments of compounds of Formula V, two R³ substituents takentogether with the carbon atoms to which they are attached form a fusedpyrazole ring optionally substituted with 1 or 2 R^(A) substituents. Insome aspects of these embodiments, R^(A) is C₁₋₄ alkyl such as methyl.

In some embodiments of compounds of Formula V, two R³ substituents takentogether with the carbon atoms to which they are attached form a fused2-oxo-oxazolidine ring, which is optionally substituted with 1 or 2R^(B) substitutents. In some aspects of these embodiments, R^(B) is C₁₋₄alkyl such as methyl.

In some embodiments, moiety

in Formula V is 1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl,1-methyl-1H-indazol-5-yl,3-methyl-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl;1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl;3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl;5-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl;4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl;2-(difluoromethyl)-1-methyl-1H-benzimidazol-5-yl;1,2-dimethyl-1H-benzimidazol-5-yl, 6-methoxypyridin-3-yl,5-fluoro-6-methoxypyridin-3-yl, 6-(2-oxopyrrolidin-1-yl)pyridin-3-yl,1-methyl-1H-benzimidazol-5-yl, 6-methoxy-5-methylpyridin-3-yl,4-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl,3-methyl-2-oxo-2,3-dihydro[1,3]oxazolo[4,5-b]pyridin-6-yl,1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl, 2-methylnicotinonitrile, or5,6-dimethylpyridin-3-yl.

In some embodiments, the compounds of the invention have Formula VIa,VIb, or VIc:

In some embodiments, the compounds of the invention have Formula VIa.

In some embodiments, the compounds of the invention have Formula VIb.

In some embodiments, the compounds of the invention have Formula VIc.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a monovalent substituent, ortwo hydrogen atoms are replaced with a divalent substituent like aterminal oxo group. It is to be understood that substitution at a givenatom is limited by valency.

Throughout the definitions, the term “C_(i-j)” indicates a range whichinclude s the endpoints, wherein i and j are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

The term “z-membered” (where z is an integer) typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is z. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1, 2, 3, 4-tetrahydro-naphthalene is an example ofa 10-membered cycloalkyl group.

As used herein, the term “C_(i-j) alkyl,” employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having i to j carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1to 4 carbon atoms, or from 1 to 3 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl.

As used herein, the term “C_(i-j) alkylene,” employed alone or incombination with other terms, means a saturated divalent linkinghydrocarbon group that may be straight-chain or branched, having i to jcarbons. In some embodiments, the alkylene group contains from 1 to 4carbon atoms, from 1 to 3 carbon atoms, or from 1 to 2 carbon atoms.Examples of alkylene moieties include, but are not limited to, chemicalgroups such as methylene, ethylene, 1,1-ethylene, 1,2-ethylene,1,3-propylene, 1,2-propylene, 1,1-propylene, isopropylene, and the like.

As used herein, the term “C_(i-j) alkoxy,” employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has i to j carbons. Example alkoxy groupsinclude methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).In some embodiments, the alkyl group has 1 to 3 carbon atoms.

As used herein, “C_(i-j) alkenyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore double carbon-carbon bonds and having i to j carbons. In someembodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms.Example alkenyl groups include, but are not limited to, ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(i-j) alkynyl,” employed alone or in combination withother terms, refers to an unsaturated hydrocarbon group having one ormore triple carbon-carbon bonds and having i to j carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6 or 2 to 4 carbon atoms.

As used herein, the term “C_(i-j) alkylamino,” employed alone or incombination with other terms, refers to a group of formula —NH(alkyl),wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments,the alkylamino group is —NH(C₁₋₄ alkyl) such as, for example,methylamino, ethylamino, or propylamino.

As used herein, the term “di-C_(i-j)-alkylamino,” employed alone or incombination with other terms, refers to a group of formula —N(alkyl)₂,wherein each of the two alkyl groups has, independently, i to j carbonatoms. In some embodiments, each alkyl group independently has 1 to 6 or1 to 4 carbon atoms. In some embodiments, the dialkylamino group is—N(C₁₋₄ alkyl)₂ such as, for example, dimethylamino or diethylamino.

As used herein, the term “C_(i-j) alkylthio,” employed alone or incombination with other terms, refers to a group of formula —S-alkyl,wherein the alkyl group has i to j carbon atoms. In some embodiments,the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments,the alkylthio group is C₁₋₄ alkylthio such as, for example, methylthioor ethylthio.

As used herein, the term “amino,” employed alone or in combination withother terms, refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic or polycyclic (e.g., having 2, 3 or4 fused rings) aromatic hydrocarbon, such as, but not limited to,phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and thelike. In some embodiments, aryl is C₆₋₁₀ aryl. In some embodiments, thearyl group is a naphthalene ring or phenyl ring. In some embodiments,the aryl group is phenyl.

As used herein, the term “aryl-C_(i-j) alkyl,” employed alone or incombination with other terms, refers to an alkyl group substituted by anaryl group. An example of an aryl-C_(i-j) alkyl group is benzyl.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “C_(i-j) cycloalkyl,” employed alone or incombination with other terms, refers to a non-aromatic cyclichydrocarbon moiety having i to j ring-forming carbon atoms, which mayoptionally contain one or more alkenylene groups as part of the ringstructure. Cycloalkyl groups can include mono- or polycyclic (e.g.,having 2, 3 or 4 fused rings) ring systems. Also include d in thedefinition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo derivatives of cyclopentane, cyclopentene,cyclohexane, and the like. A cycloalkyl group that include s a fusedaromatic ring can be attached to the core or scaffold via anyring-forming atom, including a ring-forming atom of the fused aromaticgroup. One or more ring-forming carbon atoms of a cycloalkyl group canbe oxidized to form carbonyl linkages. In some embodiments, cycloalkylis C₃₋₁₀ cycloalkyl, C₃₋₇ cycloalkyl, or C₅₋₆ cycloalkyl. Exemplarycycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, and the like. Furtherexemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

As used herein, the term “C_(i-j) cycloalkyl-C_(i-j) alkyl,” employedalone or in combination with other terms, refers to an alkyl groupsubstituted by a cycloalkyl group. An example of a C_(i-j)cycloalkyl-C_(i-j) alkyl group is cyclopropylmethyl.

As used herein, “C_(i-j) haloalkoxy,” employed alone or in combinationwith other terms, refers to a group of formula —O-haloalkyl having i toj carbon atoms. An example haloalkoxy group is OCF₃. An additionalexample haloalkoxy group is OCHF₂. In some embodiments, the haloalkoxygroup is fluorinated only. In some embodiments, the alkyl group has 1 to6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy group isC₁₋₄ haloalkoxy.

As used herein, the term “halo,” employed alone or in combination withother terms, refers to a halogen atom selected from F, Cl, I or Br. Insome embodiments, “halo” refers to a halogen atom selected from F, Cl,or Br. In some embodiments, the halo substituent is F.

As used herein, the term “C_(i-j) haloalkyl,” employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has i to j carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the haloalkyl group isfluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments,the haloalkyl group is trifluoromethyl. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “heteroaryl,” employed alone or in combinationwith other terms, refers to a monocyclic or polycyclic (e.g., having 2,3 or 4 fused rings) aromatic heterocylic moiety, having one or moreheteroatom ring members selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ringmembers. In some embodiments, the heteroaryl group has 1, 2, or 3heteroatom ring members. In some embodiments, the heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the heteroaryl grouphas 1 heteroatom ring member. In some embodiments, the heteroaryl groupis 5- to 10-membered or 5- to 6-membered. In some embodiments, theheteroaryl group is 5-membered. In some embodiments, the heteroarylgroup is 6-membered. When the heteroaryl group contains more than oneheteroatom ring member, the heteroatoms may be the same or different.The nitrogen atoms in the ring(s) of the heteroaryl group can beoxidized to form N-oxides. Exemplary heteroaryl groups include, but arenot limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, thiadiazolyl,quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl,benzisoxazolyl, imidazo[1, 2-b]thiazolyl, purinyl, triazinyl, and thelike. In some embodiments, the heteroaryl group is pyridyl,1H-indazolyl, 1H-pyrrolo[2,3-b]pyridinyl, or 1H-benzo[d]imidazolyl.

A 5-membered heteroaryl is a heteroaryl group having five ring-formingatoms comprising wherein one or more of the ring-forming atoms areindependently selected from N, O, and S. In some embodiments, the5-membered heteroaryl group has 1, 2, 3, or 4 heteroatom ring members.In some embodiments, the 5-membered heteroaryl group has 1, 2, or 3heteroatom ring members. In some embodiments, the 5-membered heteroarylgroup has 1 or 2 heteroatom ring members. In some embodiments, the5-membered heteroaryl group has 1 heteroatom ring member. Examplering-forming members include CH, N, NH, O, and S. Example five-memberedring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1, 2, 3-triazolyl,tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2,4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3,4-triazolyl, 1, 3, 4-thiadiazolyl, and 1, 3, 4-oxadiazolyl.

A 6-membered heteroaryl is a heteroaryl group having six ring-formingatoms wherein one or more of the ring-forming atoms is N. In someembodiments, the 6-membered heteroaryl group has 1, 2, or 3 heteroatomring members. In some embodiments, the 6-membered heteroaryl group has 1or 2 heteroatom ring members. In some embodiments, the 6-memberedheteroaryl group has 1 heteroatom ring member. Example ring-formingmembers include CH and N. Example six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl.

As used herein, the term “heteroaryl-C_(i-j) alkyl,” employed alone orin combination with other terms, refers to an alkyl group substituted bya heteroaryl group. An example of a heteroaryl-C_(i-j) alkyl group ispyridylmethyl.

As used herein, the term “heterocycloalkyl,” employed alone or incombination with other terms, refers to non-aromatic heterocyclic ringsystem, which may optionally contain one or more unsaturations as partof the ring structure, and which has at least one heteroatom ring memberindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heterocycloalkyl group has 1, 2, 3, or 4 heteroatomring members. In some embodiments, the heterocycloalkyl group has 1, 2,or 3 heteroatom ring members. In some embodiments, the heterocycloalkylgroup has 1 or 2 heteroatom ring members. In some embodiments, theheterocycloalkyl group has 1 heteroatom ring member. When theheterocycloalkyl group contains more than one heteroatom in the ring,the heteroatoms may be the same or different. Example ring-formingmembers include CH, CH₂, C(O), N, NH, O, S, S(O), and S(O)₂.Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2,3 or 4 fused rings) ring systems, including spiro systems. Also included in the definition of heterocycloalkyl are moieties that have one ormore aromatic rings fused to (i.e., having a bond in common with) thenon-aromatic ring, for example, 1,2,3,4-tetrahydro-quinoline,dihydrobenzofuran, and the like. A heterocycloalkyl group including afused aromatic ring can be attached to the core or scaffold via anyring-forming atom, including a ring-forming atom of the fused aromaticgroup. The S or N ring-forming atoms can be optionally “oxidized” toinclude one or two oxo groups as valency permits (e.g., sulfonyl orsulfinyl or N-oxide). One or more ring-forming carbon atoms of theheterocycloalkyl group can include an oxo moiety to form a ring-formingcarbonyl. In some embodiments, a ring-forming nitrogen atom can bequaternized. In some embodiments, the heterocycloalkyl is 5- to10-membered, 4- to 10-membered, 4- to 7-membered, 5-membered, or6-membered. Examples of heterocycloalkyl groups include 1, 2, 3,4-tetrahydro-quinolinyl, dihydrobenzofuranyl, azetidinyl, azepanyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,dihydrofuranyl, tetrahydrofuranyl, 2-oxopyrrolidinyl, 3-oxomorpholinyl,2-oxooxazolidinyl, and pyranyl. Further examples of heterocycloalkylgroups include 2,3-dihydro-1H-pyrrolyl; 2-oxo-2,3-dihydro-1H-pyrrolyl;2,3-dihydro-oxazolyl; 2-oxo-2,3-dihydro-oxazolyl;3,4-dihydro-2H-1,4-oxazinyl; 3-oxo-3,4-dihydro-2H-1,4-oxazinyl; or2,3-dihydro-furanyl. In further embodiments, the heterocycloalkyl groupis azetidinyl, piperidinyl, pyrrolidinyl, diazapanyl, ordiazaspirononanyl. In yet further embodiments, the heterocycloalkylgroup is 2,3-dihydro-1H-indolyl; 2,3-dihydro-1,3-benzoxazolyl;3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl;3,4-dihydro-2H-1,4-benzoxazinyl; or 2,3-dihydro-1-benzofuran.

As used herein, the term “heterocycloalkyl-C_(i-j) alkyl,” employedalone or in combination with other terms, refers to an alkyl groupsubstituted by a heterocycloalkyl group. An example of aheterocycloalkyl-C_(i-j) alkyl group is pyrrolidinylmethyl.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereoisomers, are intended unless otherwise indicated. Compounds ofthe present invention that contain asymmetrically substituted carbonatoms can be isolated in optically active or racemic forms. Methods onhow to prepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

When the compounds of the invention contain a chiral center, thecompounds can be any of the possible stereoisomers. In compounds with asingle chiral center, the stereochemistry of the chiral center can be(R) or (S). In compounds with two chiral centers, the stereochemistry ofthe chiral centers can each be independently (R) or (S) so theconfiguration of the chiral centers can be (R) and (R), (R) and (S); (S)and (R), or (S) and (S). In compounds with three chiral centers, thestereochemistry each of the three chiral centers can each beindependently (R) or (S) so the configuration of the chiral centers canbe (R), (R) and (R); (R), (R) and (S); (R), (S) and (R); (R), (S) and(S); (S), (R) and (R); (S), (R) and (S); (S), (S) and (R); or (S), (S)and (S).

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method include sfractional recrystallization using a chiral resolving acid which is anoptically active, salt-forming organic acid. Suitable resolving agentsfor fractional recrystallization methods are, for example, opticallyactive acids, such as the D and L forms of tartaric acid,diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malicacid, lactic acid or the various optically active camphorsulfonic acidssuch as β-camphorsulfonic acid. Other resolving agents suitable forfractional crystallization methods include stereoisomerically pure formsof α-methylbenzylamine (e.g., S and R forms, or diastereoisomericallypure forms), 2-phenylglycinol, norephedrine, ephedrine,N-methylephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, andthe like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-iminepairs, and annular forms where a proton can occupy two or more positionsof a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole.Tautomeric forms can be in equilibrium or sterically locked into oneform by appropriate substitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified. The compounds of the invention are notlimited by the manner in which they are made or formed. For example, thepresent invention include s compounds which are prepared synthetically,formed through a biological process or transformation, or a combinationthereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in a compound of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also include s pharmaceutically acceptable saltsof the compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (MeCN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17^(th) Ed., (Mack PublishingCompany, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977,66(1), 1-19, and in Stahl et al., Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (Wiley, 2002).

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD (N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA (N, N-diisopropylethylamine); DMF (N, N-dimethylformamide); Et(ethyl); EtOAc (ethyl acetate); g (gram(s)); h (hour(s)); HATU (N, N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); IPA (isopropyl alcohol); J (couplingconstant); LCMS (liquid chromatography-mass spectrometry); m(multiplet); M (molar); mCPBA (3-chloroperoxybenzoic acid); MS (Massspectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg(milligram(s)); min. (minutes(s)); mL (milliliter(s)); mmol(millimole(s)); N (normal); nM (nanomolar); NMP (N-methylpyrrolidinone);NMR (nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC(reverse phase high performance liquid chromatography); s (singlet); t(triplet or tertiary); TBS (tert-butyldimethylsilyl); tert (tertiary);tt (triplet of triplets); TFA (trifluoroacetic acid); THF(tetrahydrofuran); μg (microgram(s)); μL (microliter(s)); μ(micromolar);wt % (weight percent).

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in P. G. M. Wuts and T. W.Greene, Protective Groups in Organic Synthesis, 4^(th) Ed., Wiley &Sons, Inc., New York (2006), which is incorporated herein by referencein its entirety. Protecting groups in the synthetic schemes aretypically represented by “PG.”

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

Compounds of the invention can be prepared via the synthetic routeoutlined in Scheme 1. The commercially available starting material 1 canundergo Suzuki coupling with the boronic acid or ester of formula 2 (R═Hor alkyl) under standard Suzuki conditions (e.g., in the presence of apalladium catalyst and a base such as potassium carbonate) to affordcompound 3. Bromination of compound 3 in the presence ofN-bromosuccinimide (NBS) can give the compound of formula 4.Condensation of compound 4 with the carbonyl derivatives of formula 5(Hal is a halide such as Cl or Br) at elevated temperature can generatethe bicyclic compound of formula 6. The bromide in compound 6 can becoupled to a compound of formula 7, in which M is a boronic acid,boronic ester or an appropriately substituted metal [e.g., M is B(OR)₂,Sn(Alkyl)₄, or Zn-Hal], under standard Suzuki coupling conditions (e.g.,in the presence of a palladium catalyst and a suitable base) or standardStille coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi coupling conditions (e.g., in thepresence of a palladium catalyst) to give the derivative of formula 8.Alternatively, compound 7 can be a cyclic amine (where M is H andattached to an amine nitrogen) and the coupling of arylbromide 6 withthe cyclic amine 7 can be performed under Buchwald amination conditions(e.g., in the presence of a palladium catalyst and a base such as sodiumtert-butoxide). Convertion of the methoxy group in compound 8 tochloride can be achieved in the presence of phosphoryl chloride (POCl₃)at suitable temperature to give compound of formula 9. Displacement ofthe chloride in compound 9 with a nucleophile of formula 10 (whereinR¹-M is an alcohol or an amine, e.g., M is H which is attached to analcohol oxygen or an amine nitrogen) in the presence of a suitable basesuch as sodium hydride, sodium hydroxide, potassium carbonate ordiisopropylethylamine at elevated temperature can give compound offormula 11. Alternatively, the coupling of compound 9 with compound 10can be performed under standard Suzuki conditions (when M is boronicacid or ester), or standard Stille coupling conditions [when M isSn(Alkyl)₄], or standard Negishi coupling conditions (when M is Zn-Hal)to give compound 11.

Compounds of the invention can be prepared via the synthetic routeoutlined in Scheme 2 starting from compound 4 which can be prepared asdescribed in Scheme 1. Compound 4 can be converted to a formamidoximederivative of formula 12 by reacting with N,N-dimethylformamide dimethylacetal, followed by treatment with hydroxylamine. The formamidoximederivative 12 can undergo cyclization upon treating with trifluoroaceticanhydride (TFAA) to afford the triazole compound of formula 13. Thepreparation of compound 14 from compound 13 can be achieved usingsimilar conditions as described in Scheme 1 (i.e., conditions used forpreparation of compound 11 from compound 8).

Compounds of the invention can be prepared via the synthetic routeoutlined in Scheme 3. Bromination of compound 1 with a suitable reagentsuch as NBS can give compound 15. The amino group in compound 15 can beconverted to iodine in the presence of a suitable nitrite such asisoamyl nitrite and an iodine source such as copper iodide (CuI) to givecompound 16. Selective cyanation of compound 16 using Zn(CN)₂ in thepresence of a catalyst can deliver the pyrimidyl cyanide of formula 17.Reduction of the cyanide with a suitable reducing agent such asdiisobutylaluminium hydride (DIBAL), lithium aluminium hydride (LAH) orborane (BH₃) can afford the amine 18. Acylation of the amine 18 usingacetic formic anhydride can generate an amide intermediate 19, which canundergo cyclization upon treatment with POCl₃ to provide a bicyclicimidazole derivative of formula 20. Introduction of the ring A can beachieved by selective coupling of compound 20 with compound 7 usingsimilar conditions as described in Scheme 1 (i.e., conditions forpreparation of compound 8 from compound 6) to give compound of formula21. Suzuki coupling of compound 21 with boronic ester/acid of formula 2can give compound 22, which can be converted to the arylchloride 23 byreacting with POCl₃. Coupling of arylchloride 23 with compound 10 usingsimilar conditions as described in Scheme 1 can generate compound offormula 24.

Compounds of the invention can be prepared via the synthetic routeoutlined in Scheme 4 starting from the commercially available compound25. Introduction of the hydrazine moiety can be achieved via SNArdisplacement of the chloride in compound 25 with hydrazine to givecompound 26. A condensation reaction can be performed between compound26 with compound of formula 27 at elevated temperature to producecompound 28. Preparation of compound 29 from compound 28 can be achievedusing similar procedures as described in Scheme 3 (i.e., conditions usedfor preparation of compound 24 from compound 20).

Compounds of the invention can be prepared via the synthetic routeoutlined in Scheme 5. Selective Suzuki coupling of iodo-derivative offormula 30 with boronic acid/ester 2 under standard Suzuki couplingconditions (i.e. in the presence of a palladium catalyst and a suitablebase) can give dichloro-compound 31. Selective displacement of one ofthe chlorides in compound 31 with methoxy by reacting with sodiummethoxide can give compound 32. Bromination of compound 32 undersuitable conditions (i.e. in the presence of NBS) can give compound 33,which can react with ammonia to give the aminopyridine derivative 34.Condensation of compound 34 with compound 5 can give the bicycliccompound 35. Installation of Ring A can be achieved using similarconditions as described in Scheme 1 (i.e., conditions used forpreparation of compound 8 from compound 6) to give compound 36. Thephenol derivative 37 can be prepared by demethylation of compound 36under a suitable condition [i.e., boron tribromide (BBr₃) ortrimethylsilyl iodide (TMSI)]. Compound 38 can be prepared from compound37 via Mitsunobu reaction with an alcohol (R^(a1)—OH) or alkylation withR^(a1)-Lg (Lg is a leaving group such as halide or OMs). Alternatively,the phenol 37 can be converted to triflate 39 under suitable conditions(i.e., in the presence of triflic anhydride and a base such aspyridine). The coupling of triflate 39 with compound 10 can be performedunder standard Suzuki conditions (when M is boronic acid or ester), orstandard Stille coupling conditions [when M is Sn(Alkyl)₄], or standardNegishi coupling conditions (when M is Zn-Hal) to give compound 40.

Compounds of the invention can be prepared using the synthetic routeoutlined in Scheme 6. Condensation of aminopyridine 34 withN,N-dimethylformamide dimethyl acetal, followed by treatment withhydroxylamine can give the formamidoxime derivative of formula 41, whichcan undergo cyclization upon treating with trifluoroacetic anhydride(TFAA) to afford the triazole compound of formula 42. The preparation ofcompound 43 from compound 42 can be achieved using similar syntheticconditions as described in Scheme 5 (i.e. procedures used forpreparation of compound 40 or 38 from compound 35).

Compounds of the invention can be prepared using the synthetic routeoutlined in Scheme 7. Introduction of the hydrazine moiety can beachieved via SNAr displacement of the chloride in compound 33 withhydrazine to give compound 44. A condensation reaction can be performedbetween compound 44 with compound of formula 27 at elevated temperatureto produce compound 45. Preparation of compound 46 from compound 45 canbe achieved using similar procedures as described in Scheme 5 (i.e.procedures used for preparation of compound 40 or 38 from compound 35).

Compounds of the invention can be prepared via the synthetic routeoutlined in Scheme 8 starting from the commercially available compound47. Selective introduction of cyano group can be achieved by oxidationof the pyridine 47 with meta-chloroperoxybenzoic acid (m-CPBA) toN-oxide, followed by treatment with trimethylsilyl cyanide (TMS-CN) togive the cyano-derivative 48. Reduction of the cyanide with a suitablereducing agent such as diisobutylaluminium hydride (DIBAL), lithiumaluminium hydride (LAH) or borane (BH₃) can afford the amine 49.Acylation of the amine 49 using acetic formic anhydride can generate anamide intermediate 50, which can undergo cyclization upon treatment withPOCl₃ to provide a bicyclic imidazole derivative of formula 51.Installation of ring A can be achieved under standard cross-couplingconditions (i.e. conditions used for preparation of compound 8 fromcompound 6 as described in Scheme 1) to give compound 52. Suzukicoupling of the imidazopyridine chloride 52 with boronic acid/ester 2can give compound 53. Compound 54 can be prepared from compound 53 usingsimilar conditions as described in Scheme 5 (i.e., conditions used forthe preparation of compound 38 or 40 from compound 36).

Compounds of the invention can be prepared via the synthetic routeoutlined in Scheme 9. The commercially available starting material 1 canundergo Suzuki coupling with the boronic acid or ester of formula 2 (R═Hor alkyl) under standard Suzuki conditions (e.g., in the presence of apalladium catalyst and a base such as potassium carbonate) to affordcompound 3. Bromination of compound 3 in the presence ofN-bromosuccinimide (NBS) can give the compound of formula 4.Condensation of compound 4 with the carbonyl derivatives of formula 55(Hal is a halide such as Cl or Br) at elevated temperature can generatethe bicyclic compound of formula 60. The bromide in compound 60 can becoupled to a compound of formula 7, in which M is a boronic acid,boronic ester or an appropriately substituted metal [e.g., M is B(OR)₂,Sn(Alkyl)₄, or Zn-Hal], under standard Suzuki coupling conditions (e.g.,in the presence of a palladium catalyst and a suitable base) or standardStille coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi coupling conditions (e.g., in thepresence of a palladium catalyst) to give the derivative of formula 61.Alternatively, compound 7 can be a cyclic amine (where M is H andattached to an amine nitrogen) and the coupling of arylbromide 60 withthe cyclic amine 7 can be performed under Buchwald amination conditions(e.g., in the presence of a palladium catalyst and a base such as sodiumtert-butoxide) to yield a compound of formula 61. Convertion of themethoxy group in compound 61 to chloride can be achieved in the presenceof phosphoryl chloride (POCl₃) at suitable temperature to give compoundof formula 62. Displacement of the chloride in compound 62 with anucleophile of formula 10 (wherein R¹-M′ is an alcohol or an amine,e.g., M′ is H which is attached to an alcohol oxygen or an aminenitrogen) in the presence of a suitable base such as sodium hydride,sodium hydroxide, potassium carbonate or diisopropylethylamine atelevated temperature can give compound of formula 59. Alternatively, thecoupling of compound 62 with compound 10 can be performed under standardSuzuki conditions (when M is boronic acid or ester), or standard Stillecoupling conditions [when M is Sn(Alkyl)₄], or standard Negishi couplingconditions (when M is Zn-Hal) to give compound 59.

Compounds of the invention can be prepared via the synthetic routeoutlined in Scheme 10. The commercially available starting material 1can undergo Suzuki coupling with the boronic acid or ester of formula 2(R═H or alkyl) under standard Suzuki conditions (e.g., in the presenceof a palladium catalyst and a base such as potassium carbonate) toafford compound 3. Bromination of compound 3 in the presence ofN-bromosuccinimide (NBS) can give the compound of formula 4.Condensation of compound 4 with the carbonyl derivatives of formula 55(Hal is a halide such as Cl or Br) at elevated temperature can generatethe bicyclic compound of formula 56. The hydroxyl group in compound 56can be replaced with a halide (such as e.g. Cl), by treating compound 56with an acid halide (e.g. acid chloride, such as for example phosphorustrichloride or phosphoryl chloride (phosphorus oxychloride)) to yield acompound of formula 57. Displacement of the chloride in compound 57 witha nucleophile of formula 10 (wherein R¹-M′ is an alcohol or an amine,e.g., M′ is H which is attached to an alcohol oxygen or an aminenitrogen) in the presence of a suitable base such as sodium hydride,sodium hydroxide, potassium carbonate or diisopropylethylamine atelevated temperature can give compound of formula 58. Alternatively, thecoupling of compound 57 with compound 10 can be performed under standardSuzuki conditions (when M is boronic acid or ester), or standard Stillecoupling conditions [when M is Sn(Alkyl)₄], or standard Negishi couplingconditions (when M is Zn-Hal) to give compound 58. The bromide incompound 58 can be coupled to a compound of formula 7, in which M is aboronic acid, boronic ester or an appropriately substituted metal [e.g.,M is B(OR)₂, Sn(Alkyl)₄, or Zn-Hal], under standard Suzuki couplingconditions (e.g., in the presence of a palladium catalyst and a suitablebase) or standard Stille coupling conditions (e.g., in the presence of apalladium catalyst), or standard Negishi coupling conditions (e.g., inthe presence of a palladium catalyst) to give the derivative of formula59. Alternatively, compound 7 can be a cyclic amine (where M is H andattached to an amine nitrogen) and the coupling of arylbromide 58 withthe cyclic amine 7 can be performed under Buchwald amination conditions(e.g., in the presence of a palladium catalyst and a base such as sodiumtert-butoxide) to yield a compound of formula 59.

Methods of Use

Compounds of the invention are LSD1 inhibitors and, thus, are useful intreating diseases and disorders associated with activity of LSD1. Forthe uses described herein, any of the compounds of the invention,including any of the embodiments thereof, may be used.

The present invention is directed to a method of modulating LSD1comprising contacting the LSD1 with a compound of Formula I. The presentinvention is further directed to a method of mediating LSD1 comprisingcontacting the LSD1 with a compound of Formula I. The present inventionis further directed to a method of modulating LSD1 signaling comprisingcontacting the LSD1 with a compound of Formula I.

In some embodiments, the compounds of the invention are selective forLSD1 over LSD2, meaning that the compounds bind to or inhibit LSD1 withgreater affinity or potency, compared to LSD2. In general, selectivitycan be at least about 5-fold, at least about 10-fold, at least about20-fold, at least about 50-fold, at least about 100-fold, at least about200-fold, at least about 500-fold or at least about 1000-fold.

As inhibitors of LSD1, the compounds of the invention are useful intreating LSD1-mediated diseases and disorders. The term “LSD1-mediateddisease” or “LSD1-mediated disorder” refers to any disease or conditionin which LSD1 plays a role, or where the disease or condition isassociated with expression or activity of LSD1. The compounds of theinvention can therefore be used to treat or lessen the severity ofdiseases and conditions where LSD1 is known to play a role.

Diseases and conditions treatable using the compounds of the inventioninclude, generally cancers, inflammation, autoimmune diseases, viralinduced pathogenesis, beta-globinopathies, and other diseases linked toLSD1 activity.

Cancers treatable using compounds according to the present inventioninclude, for example, hematological cancers, sarcomas, lung cancers,gastrointestinal cancers, genitourinary tract cancers, liver cancers,bone cancers, nervous system cancers, gynecological cancers, and skincancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), and multiple myeloma.

Examplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, fibroma, lipoma, harmatoma, and teratoma.

Examplary lung cancers include non-small cell lung cancer (NSCLC),bronchogenic carcinoma (squamous cell, undifferentiated small cell,undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar)carcinoma, bronchial adenoma, chondromatous hamartoma, and mesothelioma.

Examplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Examplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Examplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Examplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Examplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), and spinal cord (neurofibroma, meningioma, glioma, sarcoma), aswell as neuroblastoma and Lhermitte-Duclos disease.

Examplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Examplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, and keloids.

The compounds of the invention can further be used to treat cancer typeswhere LSD1 may be overexpressed including, for example, breast,prostate, head and neck, laryngeal, oral, and thyroid cancers (e.g.,papillary thyroid carcinoma).

The compounds of the invention can further be used to treat geneticdisorders such as Cowden syndrome and Bannayan-Zonana syndrome.

The compounds of the invention can further be used to treat viraldiseases such as herpes simplex virus (HSV), varicella zoster virus(VZV), human cytomegalovirus, hepatitis B virus (HBV), and adenovirus.

The compounds of the invention can further be used to treatbeta-globinopathies including, for example, beta-thalassemia and sicklecell anemia.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a LSD1 protein with a compound of the inventioninclude s the administration of a compound of the present invention toan individual or patient, such as a human, having a LSD1 protein, aswell as, for example, introducing a compound of the invention into asample containing a cellular or purified preparation containing the LSD1protein.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician.

As used herein, the term “treating” or “treatment” refers to inhibitingthe disease; for example, inhibiting a disease, condition or disorder inan individual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology) orameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

As used herein, the term “preventing” or “prevention” refers topreventing the onset and development of a disease; for example,preventing a disease, condition or disorder in an individual who may bepredisposed to the disease, condition or disorder but does not yetexperience or display the pathology or symptomatology of the disease.

Combination Therapies

The compounds of the invention can be used in combination treatmentswhere the compound of the invention is administered in conjunction withother treatments such as the administration of one or more additionaltherapeutic agents. The additional therapeutic agents are typicallythose which are normally used to treat the particular condition to betreated. The additional therapeutic agents can include, e.g.,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, RAF, FAK, JAK, PIM, PI3K,PD-1, PD-L1, bromodomain, indoleamine 2,3-dioxygenase (IDO), TAM, FGFRinhibitors and other tumor directed therapies (small molecules orbiologics in nature) for treatment of LSD1-mediated diseases, disordersor conditions. The one or more additional pharmaceutical agents can beadministered to a patient simultaneously or sequentially. In someembodiments, the compounds of the present disclosure can be used incombination with a vaccine, an immunotherapy, such as LADDimmunotherapy, CRS-207 or DPX-Survivac for the treatment of cancer.

In some embodiments, the compounds of the invention can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include bromodomaininhibitors, the histone lysine methyltransferases, histone argininemethyl transferases, histone demethylases, histone deacetylases, histoneacetylases, and DNA methyltransferases. Histone deacetylase inhibitorsinclude, e.g., vorinostat.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with chemotherapeutic agents,agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. The compounds of the invention can also beused in combination with a medical therapy such as surgery orradiotherapy, e.g., gamma-radiation, neutron beam radiotherapy, electronbeam radiotherapy, proton therapy, brachytherapy, and systemicradioactive isotopes. Examples of suitable chemotherapeutic agentsinclude any of: abarelix, aldesleukin, alemtuzumab, alitretinoin,allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase,azacitidine, bendamustine, bevacizumab, bexarotene, bleomycin,bortezombi, bortezomib, busulfan intravenous, busulfan oral,calusterone, capecitabine, carboplatin, carmustine, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide,cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib,daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane,docetaxel, doxorubicin, dromostanolone propionate, eculizumab,epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycinC, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine,nofetumomab, oxaliplatin, paclitaxel, pamidronate, panobinostat,panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium,pentostatin, pipobroman, plicamycin, procarbazine, quinacrine,rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib,sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone,thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine,vincristine, vinorelbine, vorinostat, and zoledronate.

In some embodiments, biological anticancer drugs, such as antibodies andcytokines, can be combined with the compounds of the present invention.In addition, drugs modulating microenvironment or immune responses canbe combined with the compounds of the invention. Examples of such drugsinclude anti-Her2 antibodies, anti-CD20 antibodies, anti-CTLA1,anti-PD-1, anti-PDL1, and other immunotherapeutic drugs.

For treating cancer and other proliferative diseases, the compounds ofthe invention can be used in combination with targeted therapies,including JAK kinase inhibitors (Ruxolitinib, additional JAK1/2 andJAK1-selective), Pim kinase inhibitors, TAM kinase inhibitors, PI3kinase inhibitors including PI3K-delta selective (e.g., INCB50797),PI3K-gamma selective and broad spectrum PI3K inhibitors, MEK inhibitors,Cyclin Dependent kinase inhibitors, BRAF inhibitors, mTOR inhibitors,proteasome inhibitors (Bortezomib, Carfilzomib), HDAC-inhibitors(panobinostat, vorinostat), DNA methyl transferase inhibitors,dexamethasone, bromo and extra terminal family members inhibitors (forexample, bromodomain inhibitors or BET inhibitors such as INCB54329 andINCB57643), FGFR inhibitors (e.g., INCB54828, INCB62079 and INCB63904)and indoleamine 2,3-dioxygenase inhibitors (e.g., epacadostat andGDC0919).

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with a corticosteroid suchas triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone,or flumetholone.

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with an immune suppressantsuch as fluocinolone acetonide (Retisert®), rimexolone (AL-2178, Vexol,Alcon), or cyclosporine (Restasis®).

For treating autoimmune or inflammatory conditions, the compound of theinvention can be administered in combination with one or more additionalagents selected from Dehydrex™ (Holles Labs), Civamide (Opko), sodiumhyaluronate (Vismed, Lantibio/TRB Chemedia), cyclosporine (ST-603,Sirion Therapeutics), ARG101(T) (testosterone, Argentis), AGR1012(P)(Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen),15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine,doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301,Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali),oxytetracycline (Duramycin, MOLI1901, Lantibio), CF101 (2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl,Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences),ARG103 (Agentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15(Dyanmis Therapeutics), rivoglitazone (DE011, Daiichi Sanko), TB4(RegeneRx), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Science), REV1-31(Evolutec), Lacritin (Senju), rebamipide (Otsuka-Novartis), OT-551(Othera), PAI-2 (University of Pennsylvania and Temple University),pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednoletabonate, rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611(Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab,mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

For treating beta-thalassemia or sickle cell disease, the compound ofthe invention can be administered in combination with one or moreadditional agents such as Hydrea® (hydroxyurea).

In some embodiments, the compound of the invention can be administeredin combination with one or more agents selected from an antibiotic,antiviral, antifungal, anesthetic, anti-inflammatory agents includingsteroidal and non-steroidal anti-inflammatories, and anti-allergicagents. Examples of suitable medicaments include aminoglycosides such asamikacin, gentamycin, tobramycin, streptomycin, netilmycin, andkanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin,ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin;naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin;paramomycin; colistimethate; bacitracin; vancomycin; tetracyclines;rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams;cephalosporins; amphotericins; fluconazole; flucytosine; natamycin;miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen;ketorolac; suprofen; cromolyn; lodoxamide; levocabastin; naphazoline;antazoline; pheniramine; or azalide antibiotic.

Other examples of agents, one or more of which a provided LSD1 inhibitorcompound may also be combined with include: a treatment for Alzheimer'sDisease such as donepezil and rivastigmine; a treatment for Parkinson'sDisease such as L-DOPA/carbidopa, entacapone, ropinirole, pramipexole,bromocriptine, pergolide, trihexyphenidyl, and amantadine; an agent fortreating multiple sclerosis (MS) such as beta interferon (e.g., Avonex®and Rebif®), glatiramer acetate, and mitoxantrone; a treatment forasthma such as albuterol and montelukast; an agent for treatingschizophrenia such as zyprexa, risperdal, seroquel, and haloperidol; ananti-inflammatory agent such as a corticosteroid, such as dexamethasoneor prednisone, a TNF blocker, IL-1 RA, azathioprine, cyclophosphamide,and sulfasalazine; an immunomodulatory agent, includingimmunosuppressive agents, such as cyclosporin, tacrolimus, rapamycin,mycophenolate mofetil, an interferon, a corticosteroid,cyclophosphamide, azathioprine, and sulfasalazine; a neurotrophic factorsuch as an acetylcholinesterase inhibitor, an MAO inhibitor, aninterferon, an anti-convulsant, an ion channel blocker, riluzole, or ananti-Parkinson's agent; an agent for treating cardiovascular diseasesuch as a beta-blocker, an ACE inhibitor, a diuretic, a nitrate, acalcium channel blocker, or a statin; an agent for treating liverdisease such as a corticosteroid, cholestyramine, an interferon, and ananti-viral agent; an agent for treating blood disorders such as acorticosteroid, an anti-leukemic agent, or a growth factor; or an agentfor treating immunodeficiency disorders such as gamma globulin.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors. Exemplary immune checkpointinhibitors include inhibitors against immune checkpoint molecules suchas CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK,PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1and PD-L2. In some embodiments, the immune checkpoint molecule is astimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In someembodiments, the compounds provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab. In some embodiments, the anti PD-1 antibody isSHR-1210.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518 or MK-4166.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562. Insome embodiments, the OX40L fusion protein is MEDI6383.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM).

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration include s intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also include s pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. The term “unit dosageforms” refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compound may be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face masks tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted hereinabove.

The compounds of the invention can be provided with or used incombination with a companion diagnostic. As used herein, the term“companion diagnostic” refers to a diagnostic device useful fordetermining the safe and effective use of a therapeutic agent. Forexample, a companion diagnostic may be used to customize dosage of atherapeutic agent for a given subject, identify appropriatesubpopulations for treatment, or identify populations who should notreceive a particular treatment because of an increased risk of a seriousside effect.

In some embodiments, the companion diagnostic is used to monitortreatment response in a patient. In some embodiments, the companiondiagnostic is used to identify a subject that is likely to benefit froma given compound or therapeutic agent. In some embodiments, thecompanion diagnostic is used to identify a subject having an increasedrisk of adverse side effects from administration of a therapeutic agent,compared to a reference standard. In some embodiments, the companiondiagnostic is an in vitro diagnostic or imaging tool selected from thelist of FDA cleared or approved companion diagnostic devices. In someembodiments, the companion diagnostic is selected from the list of teststhat have been cleared or approved by the Center for Devices andRadiological Health.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating LSD1 in tissue samples,including human, and for identifying LSD1 ligands by inhibition bindingof a labeled compound. Accordingly, the present invention include s LSD1assays that contain such labeled compounds.

The present invention further include s isotopically-labeled compoundsof the invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2, or 3 deuterium atoms.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind LSD1 by monitoring its concentrationvariation when contacting with LSD1, through tracking of the labeling.For example, a test compound (labeled) can be evaluated for its abilityto reduce binding of another compound which is known to bind to LSD1(i.e., standard compound). Accordingly, the ability of a test compoundto compete with the standard compound for binding to LSD1 directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples were found to be inhibitorsof LSD1 as described below.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow.

Preparatory LC-MS purifications of some of the compounds prepared wereperformed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Examples Example 14-(8-(4-methylphenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Step 1: 4-(6-amino-2-methoxypyrimidin-4-yl)benzonitrile

To a mixture of 6-chloro-2-methoxypyrimidin-4-amine (Ark Pharm, cat#AK-25131: 1.3 g, 8.0 mmol), (4-cyanophenyl)boronic acid (1.41 g, 9.60mmol) and sodium carbonate (1.7 g, 16 mmol) in 1,4-dioxane (15 mL) andwater (5 mL) was addeddichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(170 mg, 0.24 mmol). The reaction mixture was purged with nitrogen thenstirred at 95° C. overnight. The reaction mixture was cooled to roomtemperature then water (20 mL) was added. The resulting precipitate wascollected via filtration then dried to give the desired product (1.7 g,94%), which was used in the next step without further purification.LC-MS calculated for C₁₂H₁₁N₄O (M+H)⁺: m/z=227.1. found 227.1.

Step 2: 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)benzonitrile

N-Bromosuccinimide (1.3 g, 7.5 mmol) was added to a solution of4-(6-amino-2-methoxypyrimidin-4-yl)benzonitrile (1.7 g, 7.5 mmol) indimethyl sulfoxide (15 mL)/acetonitrile (8 mL)/water (0.5 mL) at 0° C.The resulting mixture was stirred at 0° C. for 2 h then water (25 mL)was added. The resulting precipitate was collected via filtration thendried to give the desired product (2.1 g, 92%), which was used in thenext step without further purification. LC-MS calculated for C₁₂H₁₀BrN₄O(M+H)⁺: m/z=305.0. found 305.0.

Step 3: 4-(8-bromo-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Chloroacetaldehyde (7 M in water, 6 mL, 42 mmol) was added to a mixtureof 4-(6-amino-5-bromo-2-methoxypyrimidin-4-yl)benzonitrile (1.5 g, 4.9mmol) in isopropyl alcohol (15 mL). The resulting mixture was stirred at110° C. for 4 h then cooled to room temperature and concentrated. Theresidue was titurated with ethyl acetate to give desired product as theHCl salt (1.3 g, 84%), which was used in the next step without furtherpurification. LC-MS calculated for C₁₃H₈BrN₄O (M+H)⁺: m/z=315.0. found315.1.

Step 4: 4-(8-bromo-5-chloroimidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Phosphoryl chloride (12 mL, 130 mmol) was added to a mixture of4-(8-bromo-5-hydroxyimidazo[1,2-c]pyrimidin-7-yl)benzonitrile (1.0 g,3.2 mmol) in acetonitrile (12 mL). The resulting mixture was stirred at110° C. overnight then cooled to room temperature and concentrated. Theresidue was dissolved in methylene chloride then washed with sat'dNaHCO₃ solution, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 30% EtOAc/DCM togive the desired product (0.68 g, 64%). LC-MS calculated for C₁₃H₇BrClN₄(M+H)⁺: m/z=333.0. found 333.0.

Step 5: tert-butyl(3R)-3-({[8-bromo-7-(4-cyanophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate

Sodium hydride (49 mg, 1.2 mmol) was added to a solution of tert-butyl(3R)-3-(hydroxymethyl)piperidine-1-carboxylate (D-L Chiral Chemicals,cat #LAC-B-393: 260 mg, 1.2 mmol) in N,N-dimethylformamide (3 mL) at 0°C. The resulting mixture was stirred at room temperature for 20 min thenadded to a suspension of4-(8-bromo-5-chloroimidazo[1,2-c]pyrimidin-7-yl)benzonitrile (370 mg,1.1 mmol) in N,N-dimethylformamide (3 mL) at 0° C. The resulting mixturewas stirred at room temperature for 1 h then quenched with water andextracted with ethyl acetate. The combined extracts were washed withsat'd NaHCO₃, water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 40% EtOAc/DCM togive the desired product (0.52 g, 91%). LC-MS calculated forC₂₄H₂₇BrN₅O₃(M+H)⁺: m/z=512.1. found 512.1.

Step 6:4-{8-bromo-5-[(3R)-piperidin-3-ylmethoxy]imidazo[1,2-c]pyrimidin-7-yl}benzonitrilehydrochloride

4.0 M Hydrogen chloride in dioxane (3 mL, 12 mmol) was added to asolution of tert-butyl(3R)-3-({[8-bromo-7-(4-cyanophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate(0.52 g, 1.0 mmol) in methylene chloride (2 mL). The resulting mixturewas stirred at room temperature for 30 min then concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₁₉H₁₉BrN₅O (M+H)⁺: m/z=412.1. found 412.1.

Step 7:4-(8-bromo-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

7.0 M Formaldehyde in water (2 mL, 14 mmol) was added to a mixture of4-{8-bromo-5-[(3R)-piperidin-3-ylmethoxy]imidazo[1,2-c]pyrimidin-7-yl}benzonitrilehydrochloride (400 mg, 0.89 mmol) and N,N-diisopropylethylamine (310 μL,1.8 mmol) in methylene chloride (8 mL). The resulting mixture wasstirred at room temperature for 30 min then sodium triacetoxyborohydride(380 mg, 1.8 mmol) was added. The reaction mixture was stirred at roomtemperature for 1 h then diluted with methylene chloride, washed with 1N NaOH, water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 10% MeOH/DCM togive the desired product (0.35 g, 92%). LC-MS calculated for C₂₀H₂₁BrN₅O(M+H)⁺: m/z=426.1. found 426.1.

Step 8:4-(8-(4-methylphenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

A mixture of (4-methylphenyl)boronic acid (6.4 mg, 0.047 mmol),4-(8-bromo-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile(10. mg, 0.023 mmol), sodium carbonate (7.5 mg, 0.070 mmol), anddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (1.8 mg,0.0023 mmol) in tert-butyl alcohol (0.1 mL) and water (0.2 mL) was firstpurged with nitrogen, then heated to 105° C. and stirred for 4 h. Thereaction mixture was cooled to room temperature then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₇H₂₈N₅O (M+H)⁺: m/z=438.2. found438.2.

Example 24-(8-(4-methylphenyl)-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Step 1:4-(8-bromo-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1, Step 1-7, with tert-butyl(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (Synnovator, cat#PB00887) replacing tert-butyl(3R)-3-(hydroxymethyl)piperidine-1-carboxylate in Step 5. The crudeproduct was purified by flash chromatography on a silica gel columneluting with 0 to 10% MeOH/DCM to give the desired product. LC-MScalculated for C₁₉H₁₉BrN₅O (M+H)⁺: m/z=412.1. found 412.1.

Step 2:4-(8-(4-methylphenyl)-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

A mixture of (4-methylphenyl)boronic acid (23 mg, 0.17 mmol),4-(8-bromo-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile(35 mg, 0.085 mmol), sodium carbonate (18 mg, 0.17 mmol), anddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (6.4 mg,0.0085 mmol) in tert-butyl alcohol (0.5 mL) and water (0.3 mL) waspurged with nitrogen, then stirred at 105° C. for 4 h. The reactionmixture was cooled to room temperature then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₆N₅O (M+H)⁺: m/z=424.2. found 424.2.

Example 34-(8-(6-methoxypyridin-3-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with (6-methoxypyridin-3-yl)boronic acid (Aldrich, cat#637610) replacing (4-methylphenyl)boronic acid in Step 8. The productwas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₆H₂₇N₆O₂ (M+H)⁺:m/z=455.2. found 455.2. ¹H NMR (500 MHz, DMSO) δ 8.09-8.04 (m, 2H),7.83-7.78 (m, 2H), 7.73-7.71 (m, 1H), 7.66 (dd, J=8.6, 2.5 Hz, 1H),7.60-7.54 (m, 2H), 6.88-6.83 (m, 1H), 4.68-4.62 (m, 1H), 4.59-4.52 (m,1H), 3.86 (s, 3H), 3.71-3.63 (m, 1H), 3.49-3.41 (m, 1H), 3.00-2.78 (m,5H), 2.46-2.36 (m, 1H), 1.97-1.85 (m, 2H), 1.81-1.65 (m, 1H), 1.46-1.32(m, 1H).

Example 44-(8-[6-(dimethylamino)pyridin-3-yl]-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with [6-(dimethylamino)pyridin-3-yl]boronic acid(Combi-Blocks, cat #FA-2296) replacing (4-methylphenyl)boronic acid inStep 8. The product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₃₀N₇O (M+H)⁺: m/z=468.3. found 468.2.

Example 54-[5-{[(3R)-1-methylpiperidin-3-yl]methoxy}-8-(6-pyrrolidin-1-ylpyridin-3-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 1 with2-pyrrolidin-1-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Combi-Blocks, cat #PN-8695) replacing (4-methylphenyl)boronic acid inStep 8. The product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₂N₇O (M+H)⁺: m/z=494.3. found 494.3.

Example 64-(8-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Step 1: 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one

A mixture of 5-bromo-1-methyl-1,3-dihydro-2H-indol-2-one (Maybridge, cat#CC63010: 0.30 g, 1.3 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](500 mg,2.0 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (50 mg, 0.07 mmol) and potassiumacetate (390 mg, 4.0 mmol) in 1,4-dioxane (10 mL) was purged withnitrogen then heated at 90° C. overnight. The reaction mixture wascooled to room temperature then concentrated. The residue was purifiedby flash chromatography on a silica gel column eluting with 0 to 25%EtOAc/Hexanes to give the desired product. LC-MS calculated forC₁₅H₂₁BNO₃ (M+H)⁺: m/z=274.2. found 274.1.

Step 2: 4-(8-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one(prepared in Step 1) replacing (4-methylphenyl)boronic acid in Step 8.The product was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated forC₂₉H₂₉N₆O₂ (M+H)⁺: m/z=493.2. found 493.2.

Example 74-(8-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Step 1: 6-bromo-3-methyl-1, 3-benzoxazol-2(3H)-one

A mixture of 6-bromo-1,3-benzoxazol-2(3H)-one (Aldrich, cat #697036:0.32 g, 1.5 mmol), methyl iodide (0.28 mL, 4.5 mmol) and potassiumcarbonate (210 mg, 1.5 mmol) in acetone (3 mL) was heated to 80° C. andstirred for 3 h. The reaction mixture was cooled to room temperaturethen diluted with water and extracted with EtOAc. The combined extractswere dried over Na₂SO₄, filtered and concentrated. The residue was usedin the next step without further purification. LC-MS calculated forC₈H₇BrNO₂ (M+H)⁺: m/z=228.0. found 227.9.

Step 2: 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one

A mixture of the crude product from Step 1,4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](580 mg,2.3 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (60 mg, 0.08 mmol) and potassiumacetate (440 mg, 4.5 mmol) in 1,4-dioxane (10 mL) was purged withnitrogen then heated at 90° C. overnight. The reaction mixture wascooled to room temperature then concentrated. The residue was purifiedby flash chromatography on a silica gel column eluting with 0 to 25%EtOAc/Hexanes to give the desired product. LC-MS calculated forC₁₄H₁₉BNO₄ (M+H)⁺: m/z=276.1. found 276.2.

Step 3: 4-(8-(3-methyl-2-oxo-2, 3-dihydro-1,3-benzoxazol-6-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one(prepared in Step 2) replacing (4-methylphenyl)boronic acid in Step 8.The product was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated forC₂₈H₂₇N₆O₃ (M+H)⁺: m/z=495.2. found 495.2. ¹H NMR (500 MHz, DMSO) δ 8.07(d, J=1.4 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.71 (d, J=1.4 Hz, 1H),7.57-7.52 (m, 2H), 7.36 (d, J=1.4 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.06(dd, J=8.1, 1.5 Hz, 1H), 4.68-4.62 (m, 1H), 4.59-4.52 (m, 1H), 3.70-3.62(m, 1H), 3.47-3.40 (m, 1H), 3.35 (s, 3H), 3.00-2.77 (m, 5H), 2.46-2.37(m, 1H), 1.97-1.85 (m, 2H), 1.82-1.67 (m, 1H), 1.45-1.32 (m, 1H).

Example 84-(8-(1-methyl-1H-indazol-5-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(Adv ChemBlocks, cat #C-2063) replacing (4-methylphenyl)boronic acid inStep 8. The product was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₈N₇O (M+H)⁺: m/z=478.2. found 478.2.

Example 94-(8-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine(Combi-Blocks, cat #PN-8801) replacing (4-methylphenyl)boronic acid inStep 8. The reaction mixture was purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₃₂H₃₈N₇O (M+H)⁺: m/z=536.3. found 536.3.

Example 104-(8-{4-[2-(4-methylpiperazin-1-yl)-2-oxoethyl]phenyl}-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with1-methyl-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetyl}piperazine(Combi-Blocks, cat #PN-6945) replacing (4-methylphenyl)boronic acid inStep 8. The reaction mixture was purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₃₃H₃₈N₇O₂ (M+H)⁺: m/z=564.3. found 564.3.

Example 114-{5-{[(3R)-1-methylpiperidin-3-yl]methoxy}-8-[4-(2-morpholin-4-ylethyl)phenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

This compound was prepared using similar procedures as described forExample 1 with [4-(2-morpholin-4-ylethyl)phenyl]boronic acid(Combi-Blocks, cat #BB-5640) replacing (4-methylphenyl)boronic acid inStep 8. The reaction mixture was purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₃₂H₃₇N₆O₂ (M+H)⁺: m/z=537.3. found 537.3.

Example 124-{5-{[(3R)-1-methylpiperidin-3-yl]methoxy}-8-[4-(morpholin-4-ylmethyl)phenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

Step 1:4-(8-(4-formylphenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with (4-formylphenyl)boronic acid (Aldrich, cat #431966)replacing (4-methylphenyl)boronic acid in Step 8. The reaction mixturewas purified by flash chromatography on a silica gel column eluting with0 to 10% MeOH/DCM to give the desired product. LC-MS calculated forC₂₇H₂₆N₅O₂ (M+H)⁺: m/z=452.2. found 452.2.

Step 2:4-{5-{[(3R)-1-methylpiperidin-3-yl]methoxy}-8-[4-(morpholin-4-ylmethyl)phenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

A mixture of4-(8-(4-formylphenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile(9.0 mg, 0.020 mmol) and morpholine (20 μL, 0.2 mmol) in methylenechloride (1 mL) was stirred at room temperature for 15 min then sodiumtriacetoxyborohydride (9.0 mg, 0.043 mmol) was added. The resultingmixture was stirred at room temperature for 2 h then quenched withsaturated NaHCO₃ solution and extracted with DCM. The combined extractswere dried over Na₂SO₄ and concentrated. The residue was purified byprep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product.LC-MS calculated for C₃₁H₃₅N₆O₂ (M+H)⁺: m/z=523.3. found 523.2.

Example 13(3S)-1-[4-(7-(4-cyanophenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-8-yl)benzyl]pyrrolidine-3-carbonitrile

This compound was prepared using similar procedures as described forExample 12 with (3S)-pyrrolidine-3-carbonitrile hydrochloride (Tyger,cat #C90004) replacing morpholine in Step 2. The reaction mixture waspurified by prep-HPLC (pH=10, acetonitrile/water+NH₄OH) to give thedesired product. LC-MS calculated for C₃₂H₃₄N₇O (M+H)⁺: m/z=532.3. found532.3.

Example 144-(8-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Step 1: 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyrido[3, 2-b][1, 4]oxazine

A mixture of 7-bromo-4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(Maybridge, cat #CC62010: 300 mg, 1 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](660 mg,2.6 mmol), potassium acetate (380 mg, 3.9 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (50 mg, 0.06 mmol) in 1,4-dioxane (10 mL, 100mmol) was purged with nitrogen then heated to 90° C. and stirredovernight. The reaction mixture was cooled to room temperature thenconcentrated. The residue was purified by flash chromatography on asilica gel column eluting with 0 to 40% EtOAc/DCM to give the desiredproduct. LC-MS calculated for C₁₄H₂₂BN₂O₃ (M+H)⁺: m/z=277.2. found277.1.

Step 2: 4-(8-(4-methyl-3, 4-dihydro-2H-pyrido[3, 2-b][1,4]oxazin-7-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(prepared in Step 1) replacing (4-methylphenyl)boronic acid in Step 8.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₃₀N₇O₂ (M+H)⁺: m/z=496.2. found 496.2.

Example 154-(8-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Step 1: 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one

A mixture of7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one(Combi-Blocks, cat #FM-4852: 0.54 g, 2.0 mmol), methyl iodide (0.18 mL,2.9 mmol) and potassium carbonate (0.81 g, 5.9 mmol) inN,N-dimethylformamide (8 mL) was stirred at room temperature for 3 hthen diluted with water and extracted with EtOAc. The combined extractswere dried over Na₂SO₄, filtered and concentrated. The residue was usedin the next step without further purification. LC-MS calculated forC₁₅H₂₁BNO₄ (M+H)⁺: m/z=290.2. found 290.1.

Step 2: 4-(8-(4-methyl-3-oxo-3, 4-dihydro-2H-1,4-benzoxazin-7-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3 (4H)-one(prepared in Step 1) replacing (4-methylphenyl)boronic acid in Step 8.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₂₉N₆O₃ (M+H)⁺: m/z=509.2. found 509.2.

Example 164-{5-{[(3R)-1-methylpiperidin-3-yl]methoxy}-8-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

This compound was prepared using similar procedures as described forExample 1 with1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolidin-2-one(JPM2 Pharma, cat #JPM2-00-744) replacing (4-methylphenyl)boronic acidin Step 8. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₀N₇O₂ (M+H)⁺: m/z=508.2. found 508.2.

Example 174-(8-(1-methyl-1H-benzimidazol-5-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with (1-methyl-1H-benzimidazol-5-yl)boronic acid(Combi-Blocks, cat #FA-4841) replacing (4-methylphenyl)boronic acid inStep 8. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₈N₇O (M+H)⁺: m/z=478.2. found 478.2.

Example 184-(8-(1-methyl-1H-indazol-6-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with (1-methyl-1H-indazol-6-yl)boronic acid (Aldrich, cat#720798) replacing (4-methylphenyl)boronic acid in Step 8. The reactionmixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as the TFA salt. LC-MS calculated for C₂₈H₂₈N₇O(M+H)⁺: m/z=478.2. found 478.1.

Example 194-[5-{[(3R)-1-methylpiperidin-3-yl]methoxy}-8-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 1 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine(AstaTech, cat #37406) replacing (4-methylphenyl)boronic acid in Step 8.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₈N₇O (M+H)⁺: m/z=478.2. found 478.4.

Example 205-(7-(4-cyanophenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-8-yl)-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide

Step 1: 5-bromo-N,N-dimethyl-2, 3-dihydro-1-benzofuran-2-carboxamide

A mixture of 5-bromo-2,3-dihydro-1-benzofuran-2-carboxylic acid (0.50 g,2.0 mmol), 2.0 M dimethylamine in THF (4 mL, 8 mmol),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.2 g, 2.7 mmol) in methylene chloride (4 mL) was stirred at roomtemperature overnight then concentrated. The residue was purified byflash chromatography on a silica gel column eluting with 0 to 40%EtOAc/Hexanes to give the desired product (0.49 g, 88%). LC-MScalculated for C₁₁H₁₃BrNO₂ (M+H)⁺: m/z=270.0. found 270.0.

Step 2: N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide

A mixture of 5-bromo-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide(0.49 g, 1.8 mmol),4,4,5,5,4′,4′,5′,5′-Octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](0.51 g,2.0 mmol), potassium acetate (0.44 g, 4.5 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (70 mg, 0.09 mmol) and1,1′-Bis(diphenylphosphino)ferrocene (50 mg, 0.09 mmol) in 1,4-dioxane(9.0 mL) was purged with nitrogen then stirred at 100° C. for 3 h. Thereaction mixture was cooled to room temperature and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 50% EtOAc/Hexanes to afford the desired product. LC-MScalculated for C₁₇H₂₅BNO₄ (M+H)⁺; m/z=318.2. found 318.1.

Step 3:5-(7-(4-cyanophenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-8-yl)-N,N-dimethyl-2,3-dihydro-1-benzofuran-2-carboxamide

This compound was prepared using similar procedures as described forExample 1 with N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide(prepared in Step 2) replacing (4-methylphenyl)boronic acid in Step 8.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₃₁H₃₃N₆O₃ (M+H)⁺: m/z=537.3. found 537.3.

Example 214-(8-[6-(dimethylamino)pyridin-3-yl]-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 2 with [6-(dimethylamino)pyridin-3-yl]boronic acid(Combi-Blocks, cat #FA-2296) replacing (4-methylphenyl)boronic acid inStep 2. The reaction mixture was purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₂₆H₂₈N₇O (M+H)⁺: m/z=454.2. found 454.2.

Example 224-[5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}-8-(6-pyrrolidin-1-ylpyridin-3-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 2 with2-pyrrolidin-1-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Combi-Blocks, cat #PN-8695) replacing (4-methylphenyl)boronic acid inStep 2. The reaction mixture was purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₂₈H₃₀N₇O (M+H)⁺: m/z=480.3. found 480.3.

Example 234-(8-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 2 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one(Example 6, Step 1) replacing (4-methylphenyl)boronic acid in Step 2.The reaction mixture was purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₂₈H₂₇N₆O₂ (M+H)⁺: m/z=479.2. found 479.2.

Example 244-(8-(4-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 2 with 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine(Example 14, Step 1) replacing (4-methylphenyl)boronic acid in Step 2.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₈N₇O₂ (M+H)⁺: m/z=482.2. found 482.2.

Example 254-(8-(1-methyl-1H-benzimidazol-5-yl)-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 2 with (1-methyl-1H-benzimidazol-5-yl)boronic acid(Combi-Blocks, cat #FA-4841) replacing (4-methylphenyl)boronic acid inStep 2. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₆N₇O (M+H)⁺: m/z=464.2. found 464.2.

Example 264-(8-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 2 with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one(Example 7, Step 2) replacing (4-methylphenyl)boronic acid in Step 2.The reaction mixture was purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₂₇H₂₅N₆O₃ (M+H)⁺: m/z=481.2. found 481.2.

Example 274-(8-(1-methyl-1H-indazol-5-yl)-5-{[(3R)-1-methylpyrrolidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 2 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(Adv ChemBlocks, cat #C-2063) replacing (4-methylphenyl)boronic acid inStep 2. The reaction mixture was purified by prep-HPLC (pH=10,acetonitrile/water+NH₄OH) to give the desired product. LC-MS calculatedfor C₂₇H₂₆N₇O (M+H)⁺: m/z=464.2. found 464.3.

Example 284-[5-{[(3R)-1-methylpiperidin-3-yl]methoxy}-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine(PharmaBlock, cat #PB02930) replacing (4-methylphenyl)boronic acid inStep 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₇N₅O (M+H)⁺: m/z=479.2. found 479.2. ¹H NMR(500 MHz, CD₃OD) δ 8.38 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.21(d, J=1.9 Hz, 1H), 8.14 (s, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.65-7.58 (m,4H), 4.86-4.83 (m, 1H), 4.77-4.72 (m, 1H), 4.14 (s, 3H), 3.85-3.79 (m,1H), 3.61-3.55 (m, 1H), 3.08-2.97 (m, 2H), 2.95 (s, 3H), 2.64-2.52 (m,1H), 2.15-2.05 (m, 2H), 1.96-1.84 (m, 1H), 1.61-1.50 (m, 1H).

Example 294-[5-{[(3R)-1-ethylpiperidin-3-yl]methoxy}-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

Step 1: tert-butyl(3R)-3-({[7-(4-cyanophenyl)-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate

A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine(PharmaBlock, cat #PB02930: 127 mg, 0.492 mmol), tert-butyl(3R)-3-({[8-bromo-7-(4-cyanophenyl)imidazo[1,2-c]pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate(prepared in Example 1, Step 5: 126 mg, 0.246 mmol), sodium carbonate(52.1 mg, 0.492 mmol), anddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (19 mg,0.024 mmol) in tert-butyl alcohol (4 mL) and water (2 mL) was firstpurged with nitrogen, then stirred and heated at 105° C. for 2 h. Thereaction mixture was cooled to room temperature then diluted withmethylene chloride, washed with saturated NaHCO₃, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 10% MeOH in methylene chloride to give the desiredproduct (119 mg, 86%). LCMS calculated for C₃₁H₃₃N₈O₃ (M+H)⁺: m/z=565.3.found 565.2.

Step 2:4-{8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-[(3R)-piperidin-3-ylmethoxy]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

To a solution of tert-butyl(3R)-3-({[7-(4-cyanophenyl)-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-5-yl]oxy}methyl)piperidine-1-carboxylate(29.5 mg, 0.0522 mmol) in methylene chloride (100 μL) was addedtrifluoroacetic acid (50 μL). The resulting reaction mixture was stirredat room temperature for 30 min then concentrated. The residue was usedin the next step without further purification. LC-MS calculated forC₂₆H₂₅N₅O (M+H)⁺: m/z=465.2. found 465.2.

Step 3:4-[5-{[(3R)-ethylpiperidin-3-yl]methoxy}-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

The crude product from Step 2 was dissolved in methylene chloride (0.6mL) then N,N-diisopropylethylamine (30 μL, 0.2 mmol) was added. Theresulting mixture was stirred at room temperature for 10 min thenacetaldehyde (17 μL, 0.5 mmol) was added. The resultant reaction mixturewas stirred for 30 min then sodium triacetoxyborohydride (30 mg, 0.2mmol) was added. The reaction mixture was stirred at room temperaturefor 2 h then diluted with MeOH and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₉N₈O (M+H)⁺: m/z=493.2. found 493.3. ¹H NMR(500 MHz, CD₃OD) δ 8.40-8.35 (m, 3H), 8.15 (s, 1H), 8.01 (d, J=2.1 Hz,1H), 7.66-7.60 (m, 4H), 4.93-4.88 (m, 1H), 4.83-4.77 (m, 1H), 4.14 (s,3H), 3.91-3.83 (m, 1H), 3.69-3.60 (m, 1H), 3.30-3.22 (m, 2H), 3.06-2.91(m, 2H), 2.72-2.59 (m, 1H), 2.17-2.07 (m, 2H), 2.02-1.88 (m, 1H),1.67-1.55 (m, 1H), 1.39 (t, J=7.3 Hz, 3H).

Example 304-(8-[3-fluoro-4-(hydroxymethyl)-5-methylphenyl]-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Step 1:[2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol

This compound was prepared using similar procedures as described forExample 6 with (4-bromo-2-fluoro-6-methylphenyl)methanol (Oxchem, cat#AX8271172) replacing 5-bromo-1-methyl-1,3-dihydro-2H-indol-2-one inStep 1. The reaction mixture was filtered through celite, thenconcentrated. The crude product was used without further purification.LC-MS calculated for C₁₄H₁₉BFO₂ (M+H-H₂O)⁺: m/z=249.1. found 249.1.

Step 2:4-(8-[3-fluoro-4-(hydroxymethyl)-5-methylphenyl]-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with [2-fluoro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol replacing(4-methylphenyl)boronic acid in Step 8. The resulting mixture waspurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₈H₂₉FN₅O₂ (M+H)⁺:m/z=486.2. found 486.2. ¹H NMR (400 MHz, CD₃OD) δ 8.29 (d, J=2.1 Hz,1H), 7.95 (d, J=2.1 Hz, 1H), 7.71-7.63 (m, 4H), 7.07 (s, 1H), 6.97 (d,J=9.8 Hz, 1H), 4.86-4.83 (m, 2H, overlapped with H₂O peak), 4.76-4.72(m, 2H), 3.87-3.78 (m, 1H), 3.62-3.52 (m, 1H), 3.09-2.96 (m, 2H), 2.94(s, 3H), 2.67-2.54 (m, 1H), 2.44 (s, 3H), 2.15-2.03 (m, 2H), 2.02-1.84(m, 1H), 1.62-1.47 (m, 1H).

Example 314-(8-[3-fluoro-4-(hydroxymethyl)phenyl]-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 3-fluoro-4-hydroxymethylbenzeneboronic acid(Combi-Blocks, cat #FA-4306) replacing (4-methylphenyl)boronic acid inStep 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₇FN₅O₂(M+H)⁺: m/z=472.2. found 472.2.

Example 324-(8-[3,5-difluoro-4-(hydroxymethyl)phenyl]-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 3,5-difluoro-4-(hydroxymethyl)phenylboronic acid(Combi-Blocks, cat #BB-8390) replacing (4-methylphenyl)boronic acid inStep 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₆F2N₅O₂ (M+H)⁺: m/z=490.2. found 490.2.

Example 334-[5-{[(3R)-1-(2-cyanoethyl)piperidin-3-yl]methoxy}-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

To a solution of 2-propenenitrile (2.0 μL, 0.030 mmol) and4-{8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-[(3R)-piperidin-3-ylmethoxy]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile(prepared in Example 29, Step 2: 10 mg, 0.02 mmol) in acetonitrile (0.4mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (9 μL, 0.06 mmol). Thereaction mixture was stirred at 80° C. for 3 h. The mixture was cooledto room temperature, diluted with methanol then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₉H₂₈N₉O (M+H)⁺: m/z=518.2. found 518.1.

Example 344-[5-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]methoxy}-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

To a solution of4-{8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-5-[(3R)-piperidin-3-ylmethoxy]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile(prepared in Example 29, Step 2: 10 mg, 0.02 mmol) and 2-bromoethanol (7μL, 0.1 mmol) in N,N-dimethylformamide (0.4 mL) was added potassiumcarbonate (30 mg, 0.2 mmol). The reaction mixture was stirred at 45° C.for 2 h. The mixture was cooled to room temperature, filtered andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₈H₂₉N₈O₂ (M+H)⁺:m/z=509.2. found 509.2.

Example 354-(8-[4-(hydroxymethyl)-3-methylphenyl]-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 4-hydroxymethyl-3-methylphenylboronic acid (AurumPharmatech, cat #B-6677) replacing (4-methylphenyl)boronic acid in Step8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₃₀N₅O₂ (M+H)⁺: m/z=468.2. found 468.2.

Example 364-(8-[4-(hydroxymethyl)phenyl]-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 4-hydroxymethylbenzeneboronic acid (Combi-Blocks, cat#BB-2317) replacing (4-methylphenyl)boronic acid in Step 8. Theresulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₈N₅O₂ (M+H)⁺: m/z=454.2. found 454.2.

Example 374-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

Step 1:4-{8-bromo-5-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

To a mixture of N,N-diisopropylethylamine (0.63 mL, 3.6 mmol) and4-(8-bromo-5-chloroimidazo[1,2-c]pyrimidin-7-yl)benzonitrile (preparedin Example 1, Step 4: 600. mg, 1.80 mmol) in acetonitrile (10 mL) wasadded N,N-dimethylpiperidin-4-amine (Alfa Aesar, cat #L20176: 0.51 mL,3.6 mmol). The resulting reaction mixture was stirred at roomtemperature for 1 h then water (80 mL) was added. The resultingprecipitate was collected via filtration then washed with water anddried to give the desired product (660 mg, 86%), which was used in thenext step without further purification. LC-MS calculated for C₂₀H₂₂BrN₆(M+H)⁺: m/z=425.1. found 425.1.

Step 2:4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine(PharmaBlock, cat #PB02930: 366 mg, 1.41 mmol),4-{8-bromo-5-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile(300 mg, 0.71 mmol), sodium carbonate (150 mg, 1.41 mmol), anddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (53 mg,0.07 mmol) in tert-butyl alcohol (10 mL) and water (6 mL) was firstpurged with nitrogen, then heated to 95° C. and stirred for 3 h.

The reaction mixture was cooled to room temperature then purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₇H₂₈N₉(M+H)⁺: m/z=478.2. found478.2. ¹H NMR (400 MHz, CD₃OD) δ 8.38 (d, J=2.0 Hz, 1H), 8.33 (d, J=2.0Hz, 1H), 8.18 (d, J=2.1 Hz, 1H), 8.15 (s, 1H), 7.97 (d, J=2.1 Hz, 1H),7.67-7.57 (m, 4H), 4.43-4.33 (m, 2H), 4.14 (s, 3H), 3.69-3.57 (m, 1H),3.41-3.32 (m, 2H), 2.96 (s, 6H), 2.36-2.26 (m, 2H), 2.19-2.05 (m, 2H).

Example 384-[5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

Step 1:4-{8-bromo-5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

(3R)—N,N-dimethylpyrrolidin-3-amine (Aldrich, cat #656712: 6.8 mg, 0.060mmol) was added to a solution of4-(8-bromo-5-chloroimidazo[1,2-c]pyrimidin-7-yl)benzonitrile (preparedin Example 1, Step 4: 10 mg, 0.03 mmol) in N,N-dimethylformamide (0.2mL). The reaction mixture was microwaved at 120° C. for 10 min. and thencooled to room temperature and concentrated to dryness. The crudereaction mixture was used in the next step without further purification.LC-MS calculated for C₁₉H₂₀BrN₆ (M+H)⁺: m/z=411.1. found 411.2.

Step 2:4-[5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with4-{8-bromo-5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrilereplacing4-{8-bromo-5-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrilein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₆N₉(M+H)⁺: m/z=464.2. found 464.2.

Example 394-[5-(7-methyl-2,7-diazaspiro[4.4]non-2-yl)-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

Step 1: tert-butyl7-[8-bromo-7-(4-cyanophenyl)imidazo[1,2-c]pyrimidin-5-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylate

This compound was prepared using similar procedures as described forExample 38 with tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate(Synthonix, cat #D5983) replacing (3R)—N,N-dimethylpyrrolidin-3-amine inStep 1. The reaction mixture was concentrated and the residue was usedin the next step without further purification. LC-MS calculated forC₂₅H₂₈BrN₆O₂ (M+H)⁺: m/z=523.1. found 523.2.

Step 2: tert-butyl7-[7-(4-cyanophenyl)-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-5-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylate

This compound was prepared using similar procedures as described forExample 37, Step 2 with tert-butyl7-[8-bromo-7-(4-cyanophenyl)imidazo[1,2-c]pyrimidin-5-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylatereplacing4-{8-bromo-5-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile.The reaction mixture was diluted with methylene chloride, washed withsaturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was used in the next stepwithout further purification. LC-MS calculated for C₃₂H₃₄N₉O₂ (M+H)⁺:m/z=576.3. found 576.2.

Step 3: 4-[5-(7-methyl-2,7-diazaspiro[4.4]non-2-yl)-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

To the solution of tert-butyl7-[7-(4-cyanophenyl)-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-5-yl]-2,7-diazaspiro[4.4]nonane-2-carboxylate(20 mg) in methylene chloride (0.4 mL) was added trifluoroacetic acid(0.1 mL). The resulting mixture was stirred at room temperature for 1 hthen concentrated. The residue was dissolved in acetonitrile (0.4 mL)then N,N-diisopropylethylamine (50 μL, 0.3 mmol) was added, followed bythe addition of 7.0 M formaldehyde in water (0.08 mL, 0.6 mmol). Theresulting mixture was stirred at room temperature for 30 min then sodiumtriacetoxyborohydride (60 mg, 0.3 mmol) was added. The reaction mixturewas stirred at room temperature for 2 h then quenched with MeOH andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₈H₂₈N₉(M+H)⁺: m/z=490.2.found 490.2.

Example 40methyl[4-(7-(4-cyanophenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-8-yl)-2-fluorobenzyl]methylcarbamate

Step 1:1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-methylmethanamine

To a solution of 2.0 M methylamine in tetrahydrofuran (3 mL, 6 mmol) wasadded dropwise a solution of2-[4-(bromomethyl)-3-fluorophenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Combi-Blocks, cat #PN-5654: 200 mg, 0.6 mmol) in tetrahydrofuran (10mL). The reaction mixture was stirred at room temperature for 2 h, thenconcentrated. The crude product was used in the next step withoutfurther purification.

Step 2:methyl[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]methylcarbamate

To a solution of1-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-methylmethanamine(40 mg, 0.2 mmol) and N,N-diisopropylethylamine (0.056 mL, 0.32 mmol) inmethylene chloride (2 mL) was added methyl chloroformate (19 μL, 0.24mmol). The reaction was stirred at room temperature for 2 h, thenconcentrated. The crude product was used in the next step withoutfurther purification. LC-MS calculated for C₁₆H₂₄BFNO₄ (M+H)⁺:m/z=324.2. found 324.2.

Step 3:methyl[4-(7-(4-cyanophenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-8-yl)-2-fluorobenzyl]methylcarbamate

This compound was prepared using similar procedures as described forExample 1 withmethyl[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]methylcarbamatereplacing (4-methylphenyl)boronic acid in Step 8. The resulting mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₃₀H₃₂FN₆O₃(M+H)⁺:m/z=543.2. found 543.3.

Example 414-[5-{[(3R)-1-(2-methoxyethyl)piperidin-3-yl]methoxy}-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 34 with 1-bromo-2-methoxyethane replacing 2-bromoethanol. Theresulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₂N₈O₂ (M+H)⁺: m/z=523.3. found 523.3.

Example 424-(8-(3-amino-1-methyl-1H-indazol-5-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine(Combi-Blocks, cat #FF-5931) replacing (4-methylphenyl)boronic acid inStep 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₉N₅O (M+H)⁺: m/z=493.2. found 493.2.

Example 434-(8-(3-methyl-2-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Step 1: 5-bromo-2-[(methylamino)methyl]phenol

To a solution of 4-bromo-2-hydroxybenzaldehyde (Ark Pharm, cat#AK-24055: 800 mg, 4 mmol) and methylamine (4.0 mL, 30. mmol) in1,2-dichloroethane (20 mL, 200 mmol) was added sodiumtriacetoxyborohydride (1.3 g, 6.0 mmol). The reaction mixture wasstirred at rt for 2 h. The reaction mixture was then diluted withmethylene chloride, washed with saturated NaHCO₃. The aqueous phase wasextracted with methylene chloride. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was concentrated and usedfor next step without further purification. LC-MS calculated forC₈H₁₁BrNO₄ (M+H)⁺: m/z=216.1. found 216.1.

Step 2: 7-bromo-3-methyl-3, 4-dihydro-2H-1, 3-benzoxazin-2-one

To a solution of 5-bromo-2-[(methylamino)methyl]phenol (crude productfrom Step 1) and triethylamine (3 mL, 20 mmol) in tetrahydrofuran (30mL) was added triphosgene (1.4 g, 4.8 mmol) at 0° C. The resultingmixture was stirred for 1 h before 1M NaOH (2 mL) was added. Thereaction mixture was allowed to stir for another 1 h, then diluted withmethylene chloride, washed with saturated NaHCO₃. The aqueous phase wasextracted with methylene chloride. The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The residue was used inthe next step without further purification. LC-MS calculated forC₉H₉BrNO₂ (M+H)⁺: m/z=242.1. found 242.1.

Step 3: 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1, 3-benzoxazin-2-one

This compound was prepared using similar procedures as described forExample 6, Step 1 with7-bromo-3-methyl-3,4-dihydro-2H-1,3-benzoxazin-2-one (crude product fromStep 2) replacing 5-bromo-1-methyl-1,3-dihydro-2H-indol-2-one. Aftercooling to room temperature, the reaction mixture was concentrated,diluted with methylene chloride, washed over saturated NaHCO₃. Theaqueous phase was extracted with methylene chloride. The organic layerwas dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 25% AcOEt in hexanes to give the desired product. LC-MS calculatedfor C₁₅H₂₁BNO₄ (M+H)⁺: m/z=290.2. found 290.1.

Step 4: 4-(8-(3-methyl-2-oxo-3, 4-dihydro-2H-1,3-benzoxazin-7-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1,3-benzoxazin-2-onereplacing (4-methylphenyl)boronic acid in Step 8. The resulting mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₉H₂₉N₆O₃ (M+H)⁺:m/z=509.2. found 509.3.

Example 444-(8-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Step 1: 1, 3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one

This compound was prepared using similar procedures as described forExample 6, Step 1 with5-bromo-1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one (AurumPharmatech, cat #NE22745) replacing5-bromo-1-methyl-1,3-dihydro-2H-indol-2-one. After cooling to roomtemperature, the reaction mixture was concentrated, diluted withmethylene chloride then washed with saturated NaHCO₃. The aqueous phasewas extracted with methylene chloride. The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography on a silica gel column eluting with 0 to 4%methanol in methylene chloride to give the desired product. LC-MScalculated for C₁₅H₂₂BN₂O₃(M+H)⁺: m/z=289.2. found 289.1.

Step 2: 4-(8-(1, 3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-onereplacing (4-methylphenyl)boronic acid in Step 8. The resulting mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₉H₃₀N₇O₂ (M+H)⁺:m/z=508.2. found 508.3.

Example 454-(8-(5-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

Step 1: 6-bromo-5-fluoro-1, 3-benzoxazol-2(3H)-one

To a mixture of 2-amino-5-bromo-4-fluorophenol (0.3 g, 1 mmol) andtriethylamine (1.0 mL, 7.3 mmol) in tetrahydrofuran (20 mL) was addedtriphosgene (0.52 g, 1.7 mmol) at 0° C. and the resulting reactionmixture was stirred for 1 h before 1M NaOH (2 mL) was added. Thereaction mixture was allowed to stir for another 1 h, then diluted withmethylene chloride, washed with saturated NaHCO₃. The aqueous phase wasextracted with methylene chloride. The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The residue was used fornext step without further purification. LC-MS calculated for C₇H4BrFNO₂(M+H)⁺: m/z=231.9. found 231.9.

Step 2: 6-bromo-5-fluoro-3-methyl-1, 3-benzoxazol-2(3H)-one

To a mixture of 6-bromo-5-fluoro-1,3-benzoxazol-2(3H)-one (crude productfrom Step 1) and potassium carbonate (0.4 g, 3 mmol) in acetone (5 mL)was added methyl iodide (0.2 mL, 3 mmol). The reaction mixture washeated at 80° C. overnight then cooled to room temperature andconcentrated. The residue was purified by flash chromatography on asilica gel column eluting with 0 to 4% methanol in methylene chloride togive the desired product. LC-MS calculated for C₈H₆BrFNO₂ (M+H)⁺:m/z=246.0. found 245.9.

Step 3:5-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one

This compound was prepared using similar procedures as described forExample 6, Step 1 with6-bromo-5-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one (product from Step 2)replacing 5-bromo-1-methyl-1,3-dihydro-2H-indol-2-one. After cooling toroom temperature, the reaction mixture was concentrated, diluted withmethylene chloride, washed over saturated NaHCO₃. The aqueous phase wasextracted with methylene chloride. The combined organic layers weredried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography on a silica gel column eluting with 0 to 4%methanol in methylene chloride to give the desired product. LC-MScalculated for C₁₄H₁₈BFNO₄ (M+H)⁺: m/z=294.1. found 294.1.

Step 4: 4-(8-(5-fluoro-3-methyl-2-oxo-2, 3-dihydro-1,3-benzoxazol-6-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with5-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-onereplacing (4-methylphenyl)boronic acid in Step 8. The resulting mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₈H₂₆FN₆O₃(M+H)⁺:m/z=513.2. found 513.2. ¹H NMR (400 MHz, MeOD) δ 8.17 (d, J=1.8 Hz, 1H),7.84 (d, J=1.6 Hz, 1H), 7.70-7.62 (m, 4H), 7.30 (dd, J=5.5, 2.1 Hz, 1H),7.12 (d, J=8.8 Hz, 1H), 4.84-4.78 (m, 1H), 4.77-4.68 (m, 1H), 3.86-3.76(m, 1H), 3.63-3.53 (m, 1H), 3.42 (s, 3H), 3.08-2.96 (m, 2H), 2.94 (s,3H), 2.64-2.50 (m, 1H), 2.15-2.03 (m, 2H), 2.01-1.82 (m, 1H), 1.63-1.47(m, 1H).

Example 464-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-1H-indazol-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with (1-methyl-1H-indazol-5-yl)boronic acid (Ark Pharm, cat#AK-39590) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₉N₈(M+H)⁺: m/z=477.2. found 477.3.

Example 474-[5-[4-(dimethylamino)piperidin-1-yl]-8-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one(prepared in Example 7, Step 2) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₈N₇O₂ (M+H)⁺: m/z=494.2. found 494.2. ¹H NMR(500 MHz, CD₃OD) δ 8.17 (d, J=2.2 Hz, 1H), 7.98 (d, J=2.2 Hz, 1H),7.66-7.61 (m, 4H), 7.34 (d, J=1.3 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.16(dd, J=8.0, 1.6 Hz, 1H), 4.40-4.31 (m, 2H), 3.67-3.56 (m, 1H), 3.44 (s,3H), 3.39-3.34 (m, 2H), 2.95 (s, 6H), 2.35-2.27 (m, 2H), 2.17-2.05 (m,2H).

Example 484-[5-[4-(dimethylamino)piperidin-1-yl]-8-(6-methoxypyridin-3-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with (6-methoxypyridin-3-yl)boronic acid (Aldrich, cat#637610) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₈N₇O (M+H)⁺: m/z=454.2. found 454.2. ¹H NMR(500 MHz, CD₃OD) δ 8.16 (d, J=2.2 Hz, 1H), 8.11-8.09 (m, 1H), 7.96 (d,J=2.1 Hz, 1H), 7.71-7.68 (m, 2H), 7.66-7.61 (m, 3H), 6.94-6.89 (m, 1H),4.39-4.31 (m, 2H), 3.96 (s, 3H), 3.66-3.55 (m, 1H), 3.38-3.32 (m, 2H),2.95 (s, 6H), 2.35-2.25 (m, 2H), 2.17-2.05 (m, 2H).

Example 494-[5-[4-(dimethylamino)piperidin-1-yl]-8-(5-fluoro-6-methoxypyridin-3-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with 3-Fluoro-2-methoxypyridine-5-boronic acid (Combi-Blocks,cat #BB-8460) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₇FN₇O (M+H)⁺: m/z=472.2. found 472.2.

Example 504-{5-[4-(dimethylamino)piperidin-1-yl]-8-[6-(2-oxopyrrolidin-1-yl)pyridin-3-yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

This compound was prepared using similar procedures as described forExample 37 with1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]pyrrolidin-2-one(JPM2 Pharma, cat #JPM2-00-744) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₁N₈O (M+H)⁺: m/z=507.2. found 507.2. ¹H NMR(400 MHz, CD₃OD) δ 8.46 (d, J=8.7 Hz, 1H), 8.28 (d, J=1.7 Hz, 1H), 8.14(d, J=2.1 Hz, 1H), 7.95 (d, J=2.1 Hz, 1H), 7.80 (dd, J=8.7, 2.4 Hz, 1H),7.68 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.6 Hz, 2H), 4.42-4.29 (m, 2H), 4.12(t, J=7.1 Hz, 2H), 3.68-3.54 (m, 1H), 3.38-3.32 (m, 2H), 2.95 (s, 6H),2.69 (t, J=8.1 Hz, 2H), 2.34-2.25 (m, 2H), 2.23-2.03 (m, 4H).

Example 514-[5-[4-(dimethylamino)piperidin-1-yl]-8-(4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,4-benzoxazin-3(4H)-one (Prepared in Example 15, Step 1) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₀N₇O₂ (M+H)⁺: m/z=508.2. found 508.2. ¹H NMR(500 MHz, CD₃OD) δ 8.17 (d, J=2.2 Hz, 1H), 7.99 (d, J=2.2 Hz, 1H),7.70-7.64 (m, 4H), 7.24 (d, J=8.3 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 7.01(dd, J=8.3, 2.0 Hz, 1H), 4.68 (s, 2H), 4.39-4.30 (m, 2H), 3.66-3.56 (m,1H), 3.39 (s, 3H), 3.38-3.32 (m, 2H), 2.95 (s, 6H), 2.34-2.25 (m, 2H),2.16-2.04 (m, 2H).

Example 524-{8-[2-(difluoromethyl)-1-methyl-1H-benzimidazol-5-yl]-5-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

Step 1: 5-bromo-2-(difluoromethyl)-1-methyl-1H-benzimidazole

A mixture of 4-bromo-N1-methylbenzene-1,2-diamine (Combi-Blocks, cat#AN-3666: 0.5 g, 2.5 mmol), difluoroacetic acid (0.79 mL) and a fewdrops of concentrated hydrochloric acid was stirred at 120° C.overnight. After cooling to room temperature, the reaction mixture wasconcentrated, diluted with EtOAc, washed with saturated NaHCO₃. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₉H₈BrF₂N₂(M+H)⁺: m/z=261.0. found 261.0.

Step 2:2-(difluoromethyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole

A mixture of 5-bromo-2-(difluoromethyl)-1-methyl-1H-benzimidazole (0.59g, 2.2 mmol),4,4,5,5,4′,4′,5′,5′-Octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](860 mg,3.4 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (90 mg, 0.1 mmol) and potassiumacetate (660 mg, 6.8 mmol) in 1,4-dioxane (20 mL) was purged withnitrogen then heated at 90° C. overnight. After cooling to roomtemperature, the reaction mixture was concentrated. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 15% AcOEt in hexanes to give the desired product. LC-MS calculatedfor C₁₅H₂₀BF₂N₂O₂ (M+H)⁺: m/z=309.2. found 309.2.

Step 3:4-{8-[2-(difluoromethyl)-1-methyl-1H-benzimidazol-5-yl]-5-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

This compound was prepared using similar procedures as described forExample 37 with 2-(difluoromethyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₂₉F2N₈ (M+H)⁺: m/z=527.2. found 527.2. ¹H NMR(500 MHz, CD₃OD) δ 8.18 (d, J=2.2 Hz, 1H), 7.96 (d, J=2.2 Hz, 1H),7.84-7.80 (m, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.62-7.57 (m, 4H), 7.36 (dd,J=8.5, 1.5 Hz, 1H), 7.17 (t, J=52.3 Hz, 1H), 4.41-4.31 (m, 2H), 4.05 (s,3H), 3.68-3.56 (m, 1H), 3.40-3.32 (m, 2H), 2.96 (s, 6H), 2.36-2.26 (m,2H), 2.19-2.06 (m, 2H).

Example 534-[5-[4-(dimethylamino)piperidin-1-yl]-8-(6-methoxy-5-methylpyridin-3-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with (6-methoxy-5-methylpyridin-3-yl)boronic acid(Combi-Blocks, cat #BB-6068) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₃₀N₇O (M+H)⁺: m/z=468.2. found 468.2.

Example 544-[5-[4-(dimethylamino)piperidin-1-yl]-8-(5-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with5-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one(Prepared in Example 45, Step 3) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₇FN₇O₂(M+H)⁺: m/z=512.2. found 512.2.

Example 554-[5-{1[(3R)-1-ethylpiperidin-3-yl]methoxy}-8-(3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 29 with3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one(prepared in Example 7, Step 2) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 1. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₂₉N₆O₃ (M+H)⁺: m/z=509.2. found 509.3.

Example 564-[5-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]methoxy}-8-(6-methoxypyridin-3-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 34 with (6-methoxypyridin-3-yl)boronic acid (Aldrich, cat#637610) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₉N₆O₃ (M+H)⁺: m/z=485.2. found 485.2.

Example 574-(8-(5-fluoro-6-methoxypyridin-3-yl)-5-{[(3R)-1-(2-hydroxyethyl)piperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 34 with 3-fluoro-2-methoxypyridine-5-boronic acid (Combi-Blocks,cat #BB-8460) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₈FN₆O₃(M+H)⁺: m/z=503.2. found 503.2.

Example 584-[5-[4-(dimethylamino)piperidin-1-yl]-8-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

Step 1: 1-(benzyloxy)-3-fluoro-2-nitrobenzene

A mixture of 1,3-difluoro-2-nitrobenzene (1 g, 6 mmol), benzyl alcohol(0.81 mL, 7.8 mmol), potassium carbonate (1.79 g, 13.0 mmol) inN,N-dimethylformamide (5 mL) was heated at 60° C. for 18 h. The reactionmixture was cooled to room temperature then diluted with EtOAc andwashed with water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 20% EtOAc inHexanes to give the desired product.

Step 2: 2-(benzyloxy)-6-fluoroaniline

A mixture of 1-(benzyloxy)-3-fluoro-2-nitrobenzene (2 g, 8 mmol), tindichloride (4 g, 20 mmol), hydrogen chloride (1M in water, 4.8 mL, 4.8mmol) in ethanol (25 mL) was refluxed for 18 h. The mixture was cooledto room temperature then concentrated. The residue was dissolved inEtOAc and water then adjusted to basic with NaOH. The precipitate wasfiltered and the organic phase was separated then dried over Na₂SO₄ andconcentrated. The residue was purified by flash chromatography on asilica gel column eluting with 0 to 20% EtOAc in Hexanes to give thedesired product. LC-MS calculated for C₁₃H₁₃FNO (M+H)⁺: m/z=218.1. found218.1.

Step 3: 2-(benzyloxy)-4-bromo-6-fluoroaniline

Bromine (0.20 mL, 3.8 mmol) was added to a mixture of2-(benzyloxy)-6-fluoroaniline (650 mg, 3.0 mmol) in methanol (2.27 mL)and acetic acid (0.76 mL) at 0° C. The mixture was stirred at 0° C. for4 h then concentrated. The residue was dissolved in EtOAc then washedwith 1N NaOH, water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was used in the next step withoutfurther purification. LC-MS calculated for C₁₃H₁₂BrFNO (M+H)⁺:m/z=296.0. found 296.0.

Step 4: 2-amino-5-bromo-3-fluorophenol

To a solution of 2-(benzyloxy)-4-bromo-6-fluoroaniline (900 mg, 3 mmol)in tetrahydrofuran (6.0 mL) was added platinum dioxide (55 mg, 0.24mmol). The resulting mixture was purged with H₂, then stirred at roomtemperature overnight under 1 atm of H₂. The reaction mixture wasfiltered then concentrated. The residue was used in the next stepwithout further purification. LC-MS calculated for C₆H₆BrFNO (M+H)⁺:m/z=206.0. found 206.0.

Step 5: 6-bromo-4-fluoro-1, 3-benzoxazol-2(3H)-one

2-Amino-5-bromo-3-fluorophenol (0.2 g, 1 mmol) was dissolved intetrahydrofuran (10 mL) at 0° C. then triethylamine (0.68 mL, 4.8 mmol)was added, followed by triphosgene (0.34 g, 1.2 mmol). The mixture wasstirred at 0° C. for 1 h, then 1.0 M sodium hydroxide in water (1.9 mL,1.9 mmol) was added. The resulting mixture was stirred at roomtemperature for 1 h then diluted with EtOAc and washed with water andbrine. The organic layer was dried over Na₂SO₄ and the solvents wereremoved under reduced pressure. The residue was used in the next stepwithout further purification.

Step 6: 6-bromo-4-fluoro-3-methyl-1, 3-benzoxazol-2(3H)-one

A mixture of 6-bromo-4-fluoro-1,3-benzoxazol-2(3H)-one (crude productfrom Step 5), potassium carbonate (0.3 g, 2 mmol) and methyl iodide (0.1mL, 2 mmol) in acetone (3 mL) was heated at 80° C. for overnight. Thereaction mixture was cooled to room temperature then concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 25% EtOAc in Hexanes to give the desired product.LC-MS calculated for C₈H₆BrFNO (M+H)⁺: m/z=246.0. found 245.9.

Step 7:4-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one

A mixture of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (10 mg, 0.02 mmol),6-bromo-4-fluoro-3-methyl-1,3-benzoxazol-2(3H)-one (90 mg, 0.4 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](140 mg,0.55 mmol) and potassium acetate (100 mg, 1 mmol) in 1,4-dioxane (3 mL)was purged with nitrogen then stirred at 90° C. for overnight. Thereaction mixture was cooled to room temperature then diluted with EtOAcand washed with water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 25% EtOAc inHexanes to give the desired product. LC-MS calculated for C₁₄H₁₈BFNO₄(M+H)⁺: m/z=294.1. found 294.1.

Step 8:4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-1, 3-benzoxazol-6-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with4-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-onereplacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₇FN₇O₂(M+H)⁺: m/z=512.2. found 512.2.

Example 594-(8-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with4-fluoro-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2(3H)-one(prepared in Example 58, Step 7) replacing (4-methylphenyl)boronic acidin Step 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₂₆FN₆O₃(M+H)⁺: m/z=513.2. found 513.2.

Example 604-[5-[4-(dimethylamino)piperidin-1-yl]-8-(3-methyl-2-oxo-2,3-dihydro[1,3]oxazolo[4,5-b]pyridin-6-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

Step 1: 6-bromo-3-methyl[1, 3]oxazolo[4,5-b]pyridin-2(3H)-one

To a solution of 6-bromo[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (Ark Pharm,cat #AK-24539: 0.394 g, 1.83 mmol) in N,N-dimethylformamide (5 mL) at−40 OC was added sodium hydride (60 wt % in mineral oil, 290 mg, 7.3mmol). The resulting mixture was stirred at −40° C. for 1 hour thenmethyl iodide (1.14 mL, 18.3 mmol) was added dropwise. The reactionmixture was stirred at −40° C. for another 2 hours, then warmed to 0° C.and quenched by saturated NH₄Cl aqueous solution. The mixture wasextracted with EtOAc, then DCM/iPrOH (2:1). The combined extracts weredried over Na₂SO₄, filtered and concentrated. The residue was used inthe next step without further purification. LC-MS calculated forC₇H₆BrN₂O₂(M+H)⁺: m/z=229.0. found 229.0.

Step 2: 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)[1,3]oxazolo[4, 5-b]pyridin-2(3H)-one

A mixture of 6-bromo-3-methyl[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (0.15g, 0.66 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](250 mg,0.98 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (30 mg, 0.03 mmol) and potassiumacetate (190 mg, 2.0 mmol) in 1,4-dioxane (6 mL) was purged withnitrogen then heated at 90° C. overnight. After cooling to roomtemperature, the reaction mixture was concentrated. The crude materialwas purified by flash chromatography on a silica gel column eluting with0 to 5% MeOH in DCM to give the desired product. LC-MS calculated forC₁₃H₁₈BN₂O₄(M+H)⁺: m/z=277.1. found 277.1.

Step 3: 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(3-methyl-2-oxo-2,3-dihydro[1, 3]oxazolo[4,5-b]pyridin-6-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-onereplacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₇N₅O₂ (M+H)⁺: m/z=495.2. found 495.2.

Example 614-(8-(3-methyl-2-oxo-2,3-dihydro[1,3]oxazolo[4,5-b]pyridin-6-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)[1,3]oxazolo[4,5-b]pyridin-2(3H)-one (prepared in Example 60, Step 2) replacing(4-methylphenyl)boronic acid in Step 8. The resulting mixture waspurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₇H₂₆N₇O₃ (M+H)⁺:m/z=496.2. found 496.2.

Example 624-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one(Example 6, Step 1) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₀N₇O (M+H)⁺: m/z=492.3. found 492.2.

Example 634-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1,2-dimethyl-1H-benzimidazol-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

Step 1:1,2-dimethyl-5-(4,4,5,5-tetramethyl-3,2-dioxaborolan-2-yl)-1H-benzimidazole

A mixture of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (40 mg, 0.04 mmol),5-bromo-1,2-dimethyl-1H-benzimidazole (200 mg, 0.9 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](340 mg,1.3 mmol) and potassium acetate (300 mg, 3 mmol) in 1,4-dioxane (7 mL)was purged with nitrogen then stirred at 90° C. overnight. The reactionmixture was cooled to room temperature then concentrated. The residuewas purified by flash chromatography eluting with 0 to 30% MeOH in DCMto give the desired product. LC-MS calculated for C₁₅H₂₂BN₂O₂(M+H)⁺:m/z=273.2. found 273.2.

Step 2: 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1,2-dimethyl-1H-benzimidazol-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazolereplacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₁N₈(M+H)⁺: m/z=491.3. found 491.3.

Example 644-(8-[2-(difluoromethyl)-1-methyl-1H-benzimidazol-5-yl]-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with2-(difluoromethyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole(prepared in Example 52, Step 2) replacing (4-methylphenyl)boronic acidin Step 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₂₈F₂N₇O (M+H)⁺: m/z=528.2. found 528.2.

Example 654-(8-(1,2-dimethyl-1H-benzimidazol-5-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with1,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazole(Prepared in Example 63, Step 1) replacing (4-methylphenyl)boronic acidin Step 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₉H₃₀N₇O (M+H)⁺: m/z=492.3. found 492.2.

Example 665-{7-(4-cyanophenyl)-5-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-8-yl}-2-methylnicotinonitrile

Step 1:2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile

A mixture of 5-bromo-2-methylnicotinonitrile (Combi-Blocks, cat#PY-1861: 100 mg, 0.50 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](140 mg,0.55 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (20 mg, 0.02 mmol) and potassiumacetate (150 mg, 1.5 mmol) in 1,4-dioxane (5 mL) was purged withnitrogen then heated at 90° C. overnight. After cooling to roomtemperature, the reaction mixture was concentrated. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 15% AcOEt in hexanes to give the desired product. LC-MS calculatedfor C₁₃H₁₈BN₂O₂(M+H)⁺: m/z=245.2. found 245.2.

Step 2:5-{7-(4-cyanophenyl)-5-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-8-yl}-2-methylnicotinonitrile

This compound was prepared using similar procedures as described forExample 37 with2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrilereplacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₇N₈ (M+H)⁺: m/z=463.2. found 463.2.

Example 67 Methyl(5-{7-(4-cyanophenyl)-5-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-8-yl}pyridin-2-yl)methylcarbamate

Step 1: methyl (5-bromopyridin-2-yl)methylcarbamate

To a solution of 5-bromo-N-methylpyridin-2-amine (Combi-Blocks, cat#PY-1235: 138 mg, 0.738 mmol) in tetrahydrofuran (4 mL) was added cesiumcarbonate (288 mg, 0.885 mmol) and methyl chloroformate (285 μL, 3.69mmol). The resulted mixture was heated for 12 h at 50° C., then dilutedwith ethyl acetate, filtered, and concentrated. The crude product wasused without further purification. LC-MS calculated forC₈H₁₀BrN₂O₂(M+H)⁺: m/z=245.0. found 245.0.

Step 2: methylmethyl[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate

This compound was prepared using similar procedures as described forExample 6, Step 1 with methyl (5-bromopyridin-2-yl)methylcarbamatereplacing 5-bromo-1-methyl-1,3-dihydro-2H-indol-2-one. The reactionmixture was filtered through celite, and then concentrated. The crudeproduct was used in the next step without further purification.

Step 3: methyl(5-{7-(4-cyanophenyl)-5-[4-(dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-8-yl}pyridin-2-yl)methylcarbamate

This compound was prepared using similar procedures as described forExample 37 with methylmethyl[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamatereplacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₃₁N₅O₂ (M+H)⁺: m/z=511.3. found 511.2.

Example 684-[5-[4-(dimethylamino)piperidin-1-yl]-8-(5,6-dimethylpyridin-3-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 37 with2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Combi-Blocks, cat #FM-6236) replacing1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridinein Step 2. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₃₀N₇(M+H)⁺: m/z=452.3. found 452.2.

Example 694-(8-(6-methoxy-5-methylpyridin-3-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with (6-methoxy-5-methylpyridin-3-yl)boronic acid (AurumPharmatech, cat #A-3579) replacing (4-methylphenyl)boronic acid in Step8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₉N₆O₂ (M+H)⁺: m/z=469.2. found 469.2.

Example 705-(7-(4-cyanophenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-8-yl)-2-methylnicotinonitrile

This compound was prepared using similar procedures as described forExample 1 with2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile(Example 66, Step 1) replacing (4-methylphenyl)boronic acid in Step 8.The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₇H₂₆N₇O (M+H)⁺: m/z=464.2. found 464.2.

Example 714-(8-[3-(hydroxymethyl)-4-methylphenyl]-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with[2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanol(Combi-Blocks, cat #FM-2080) replacing (4-methylphenyl)boronic acid inStep 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₃₀N₅O₂ (M+H)⁺: m/z=468.2. found 468.2.

Example 724-(8-[2-(hydroxymethyl)-4-methylphenyl]-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with [2-(hydroxymethyl)-4-methylphenyl]boronic acid(Combi-Blocks, cat #21-2055) replacing (4-methylphenyl)boronic acid inStep 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₈H₃₀N₅O₂ (M+H)⁺: m/z=468.2. found 468.2.

Example 734-[5-{[(3R)-1-methylpiperidin-3-yl]methoxy}-8-(6-methylpyridin-3-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

This compound was prepared using similar procedures as described forExample 1 with2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Combi-Blocks, cat #PN-5068) replacing (4-methylphenyl)boronic acid inStep 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₇N₆O (M+H)⁺: m/z=439.2. found 439.2.

Example 744-(8-(5-fluoro-6-methylpyridin-3-yl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

This compound was prepared using similar procedures as described forExample 1 with3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(PharmaBlock Inc, cat #PBS07313) replacing (4-methylphenyl)boronic acidin Step 8. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₆FN₆O (M+H)⁺: m/z=457.2. found 457.2.

Example 75Methyl[4-(7-(4-cyanophenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-8-yl)-2-fluorophenyl]methylcarbamate

Step 1: methyl (4-bromo-2-fluorophenyl)methylcarbamate

To a solution of 4-bromo-2-fluoro-N-methylaniline hydrochloride(Combi-Blocks, cat #HC-3277: 100 mg, 0.4 mmol) andN,N-diisopropylethylamine (220 μL, 1.2 mmol) in methylene chloride (0.3mL, 5 mmol) was added methyl chloroformate (38 μL, 0.50 mmol). Theresultant mixture was stirred at room temperature overnight, then wasquenched with saturated NaHCO₃. The aqueous phase was extracted withmethylene chloride, and the organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 40% EtOAc inhexanes to give the desired product.

Step 2:methyl[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylcarbamate

A mixture of methyl (4-bromo-2-fluorophenyl)methylcarbamate (58 mg, 0.22mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](62mg, 0.24 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (9 mg, 0.01 mmol) and potassium acetate (65mg, 0.66 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen thenheated at 90° C. overnight. After cooling to room temperature, thereaction mixture was concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 15% AcOEt inhexanes to give the desired product. LC-MS calculated for C₁₅H₂₂BFNO₄(M+H)⁺: m/z=310.2. found 310.2.

Step 3:methyl[4-(7-(4-cyanophenyl)-5-{[(3R)-1-methylpiperidin-3-yl]methoxy}imidazo[1,2-c]pyrimidin-8-yl)-2-fluorophenyl]methylcarbamate

This compound was prepared using similar procedures as described forExample 1 withmethyl[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylcarbamatereplacing (4-methylphenyl)boronic acid in Step 8. The resulting mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₉H₃₀FN₆O₃(M+H)⁺:m/z=529.2. found 529.2.

TABLE 2 The compounds in Table 2 were prepared using analogousprocedures as in Example 75 using the appropriate Suzuki couplingpartners. LCMS Example Name/¹H NMR Structure (M + H)⁺ Salt  767-(7-(4-cyanophcnyl)-5-{[(3R)-1- methylpiperidin-3-yl]methoxy}imidazo[1,2- c]pyrimidin-8-yl)-N,N-dimethyl-2,3-dihydro-1,4-benzodioxine-2- carboxamide

553.2 TFA  77 4-(8-(1-mcthyl-2.3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-{[(3R)- 1-methylpiperidin-3-yl]methoxy}imidazo[1,2- c]pyrimidin-7-yl)benzonitrile

480.2 None  78 4-[5-{[(3R)-1-methylpiperidin-3-yl]methoxy}-8-(8-methyl-5,6,7,8- tetrahydro-1,8-naphthyridin-3-yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

494.3 TFA  79 4-(8-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-5-{[(3R)-1- methylpiperidin-3-yl]methoxy}imidazo[1,2- c]pyrimidin-7-yl)benzonitrile

507.2 TFA  80 4-(8-[3-fluoro-4-(morpholin-4-ylmethyl)phenyl]-5-{[(3R)-1- methylpiperidin-3- yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

541.2 TFA  81 4-[5-{[(3R)-1-(2- cyanoethyl)piperidin-3-yl]methoxy}-8-(5-fluoro-6-methoxypyridin-3- yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

512.2 TFA  82 4-{8-[6-(dimethylamino)-5- fluoropyridin-3-yl]-5-[4-(dimethylamino)piperidin-1- yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

485.3 TFA  83 4-[5-{[(3R)-1-(2- cyanoethyl)piperidin-3-yl]methoxy}-8-(3-methyl-2-oxo-2,3-dihydro-1,3- benzoxazol-6-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

534.2 TFA  84 N-[4-(7-(4-cyanophenyl)-5-{[(3R)-1- methylpiperidin-3-yl]methoxy}imidazo[1,2- c]pyrimidin-8-yl)-2-fluorobenzyl]-N-methylmethanesulfonamide

563.2 TFA  85 N-[4-(7-(4-cyanophenyl)-5-{[(3R)-1- methylpiperidin-3-yl]methoxy}imidazo[1,2- c]pyrimidin-8-yl)-2-fluorobenzyl]-N,N′,N′-trimethylurea

556.2 TFA  86 N-[4-(7-(4-cyanophenyl)-5-{[(3R)-1- methylpiperidin-3-y1]methoxy}imidazo[1,2- c]pyrimidin-8-yl)benzyl]-N,N′,N′- trimethylurea

538.2 TFA  87 methyl [4-(7-(4-cyanophenyl)-5-{[(3R)-1-methylpiperidin-3- yl]methoxy}imidazo[1,2- c]pyrimidin-8-yl)benzyl]methylcarbamate

525.5 TFA  88 4-(8-(5-chloro-6-methoxypyridin-3-yl)-5-{[(3R)-1-methylpiperidin-3- yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

489.2 TFA  89 4-{5-[4-(dimethylamino)piperidin-1-yl]-8-[3-fluoro-4-(hydroxymethyl)-5- methylphenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

485.2 TFA  90 4-{8-[3,5-difluoro-4- (hydroxymethyl)phenyl]-5-[4-(dimethylamino)piperidin-1- yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

489.2 TFA  91 4-{5-[4-(dimethylamino)piperidin-1-yl]-8-[4-(hydroxymethyl)-3- methylphenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

467.2 TFA  92 4-(8-(5-chloro-6-methylpyridin-3-yl)-5-{[(3R)-1-methylpiperidin-3- yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

473.2 TFA  93 4-(8-[3-(1-hydroxyethyl)-4- methylphenyl]-5-{[(3R)-1-methylpiperidin-3- yl]methoxy}imidazo[1,2- c]pyrimidin-7-yl)benzonitrile

482.2 TFA  94 4-(8-[4-(methoxymethyl)phenyl]-5-{[(3R)-1-methylpiperidin-3- yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

468.2 TFA  95 4-(8-[2-fluoro-4-(morpholin-4-ylmethyl)phenyl]-5-{[(3R)-1- methylpiperidin-3- yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

541.3 None  96 5-(7-(4-cyanophenyl)-5-{[(3R)-1- methylpiperidin-3-yl]methoxy}imidazo[1,2- c]pyrimidin-8-yl)-2- methylbenzonitrile

463.2 TFA  97 N-(4-{7-(4-cyanophenyl)-5-[4- (dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-8-yl}-2- fluorobenzyl)-N,N′,N′-trimethylurea

555.2 TFA  98 4-{5-[4-(dimethylamino)piperidin-1-yl]-8-[3-fluoro-4-(morpholin-4- ylmethyl)phenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

540.2 TFA  99 4-{5-{[(3R)-1-ethylpiperidin-3-yl]methoxy}-8-[3-(hydroxymethyl)- 4-methylphenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

482.2 TFA 100 4-{5-[(3R)-3- (dimethylamino)pyrrolidin-1-yl]-8-[3-(hydroxymethyl)-4- methylphenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

453.2 TFA 101 4-(8-[3-chloro-4- (hydroxymethyl)phenyl]-5-{[(3R)-1-methylpiperidin-3- yl]methoxy}imidazo[1,2- c]pyrimidin-7-yl)benzonitrile

488.2 TFA 102 4-{5-[4-(dimethylamino)piperidin-1-yl]-8-[3-(hydroxymethyl)-4- methylphenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

467.2 TFA 103 4-{8-(5-chloro-6-methylpyridin-3-yl)-5-[4-(dimethylamino)piperidin-1- yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

472.2 TFA 104 4-{8-(5-chloro-6-methoxypyridin-3-yl)-5-[4-(dimethylamino)piperidin-1- yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

488.2 TFA 105 5-{7-(4-cyanophenyl)-5-[4- (dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-8-yl}-2- methoxynicotinonitrile

479.2 TFA 106 methyl [5-(7-(4-cyanophenyl)-5-{[(3R)-1-methylpiperidin-3- yl]methoxy}imidazo[1,2- c]pyrimidin-8-yl)-2-methylphenyl]methylcarbamate

525.2 TFA 107 4-(8-(6-ethylpyridin-3-yl)-5-{[(3R)- 1-methylpiperidin-3-yl]methoxy}imidazo[1,2- c]pyrimidin-7-yl)benzonitrile

453.2 TFA 108 4-(8-(6-isopropylpyridin-3-yl)-5-{[(3R)-1-methylpiperidin-3- yl]methoxy}imidazo[1,2-c]pyrimidin-7-yl)benzonitrile

467.2 None 109 4-{5-{[(3R)-1-ethylpiperidin-3-yl]methoxy}-8-[3-fluoro-4- (hydroxymethyl)-5- methylphenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

500.2 TFA 110 4-{5-[(3R)-3- (dimethylamino)pyrrolidin-1-yl]-8-[3-fluoro-4-(hydroxymethyl)-5- methylphenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

471.2 TFA 111 4-{5-[4-(dimethylamino)piperidin-1-yl]-8-[2-(hydroxymethyl)-4- methylphenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

467.2 TFA 112 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(6-methylpyridin-3- yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

438.2 TFA 113 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(5-fluoro-6-methylpyridin-3- yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile ¹H NMR (500 MHz, CD₃OD) δ 8.14 (m, 2H), 7.95 (d, J = 2.0Hz, 1H), 7.73-7.67 (m, 3H), 7.64- 7.58 (m, 2H), 4.37 (d, J = 13.7 Hz,2H), 3.61 (m, 1H), 3.39-3.31 (m, 2H), 2.95 (s, 6H), 2.57 (d, J = 2.8 Hz,3H), 2.29 (d, J = 11.1 Hz, 2H), 2.09 (m, 2H).

456.2 TFA 114 methyl (4-{7-(4-cyanophenyl)-5-[4-(dimethylamino)piperidin-1- yl]imidazo[1,2-c]pyrimidin-8-yl}phenyl)methylcarbamate

510.2 TFA 115 N-(5-{7-(4-cyanophenyl)-5-[4- (dimethylamino)piperidin-1-yl]imidazo[1,2-c]pyrimidin-8- yl}pyridin-2-yl)-N-methylmethanesulfonamide

531.2 TFA 116 methyl (4-{7-(4-cyanophenyl)-5-[4-(dimethylamino)piperidin-1- yl]imidazo[1,2-c]pyrimidin-8-yl}-2-fluorophenyl)methylcarbamate

528.2 TFA 117 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(6-ethoxypyridin-3- yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

468.2 TFA 118 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(6-isopropylpyridin-3- yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

466.2 TFA 119 4-{5-{[(3R)-1-ethylpiperidin-3-yl]methoxy}-8-[2-(hydroxymethyl)- 4-methylphenyl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

482.2 TFA 120 4-{8-(1,3-benzothiazol-5-yl)-5-[4-(dimethylamino)piperidin-1- yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

480.1 TFA 121 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(3-hydroxy-2,3-dihydro-1H- inden-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

479.3 TFA 122 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(2-hydroxy-2,3-dihydro-1H- inden-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

479.2 TFA 123 4-(8-(3-hydroxy-2,3-dihydro-1H- inden-5-yl)-5-{[(3R)-1-methylpiperidin-3- yl]methoxy}imidazo[1,2- c]pyrimidin-7-yl)benzonitrile

480.2 TFA 124 4-(8-(2-hydroxy-2,3-dihydro-1H- inden-5-yl)-5-{[(3R)-1-methylpiperidin-3- yl]methoxy}imidazo[1,2- c]pyrimidin-7-yl)benzonitrile

480.2 TFA 125 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-1H-pyrrolo[2,3- b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

477.2 TFA 126 4-{5-[4-(dimethylamino)piperidin-1-yl]-8-quinoxalin-6-ylimidazo[1,2- c]pyrimidin-7-yl}benzonitrile

475.2 TFA 127 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(4-fluoro-1,3-dimethyl-2-oxo- 2,3-dihydro-1H-benzimidazol-5-yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

525.2 TFA 128 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(7-fluoro-1,3-dimethyl-2-oxo- 2,3-dihydro-1H-benzimidazol-5-yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

525.2 TFA 129 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(6-fluoro-1,3-dimethyl-2-oxo- 2,3-dihydro-1H-benzimidazol-5-yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

525.2 TFA 130 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

506.2 TFA 131 4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-2-oxo-1,2,3,4- tetrahydroquinolin-7-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile

506.2 TFA 132 4-{8-[5-(difluoromethyl)-6- methylpyridin-3-yl]-5-[4-(dimethylamino)piperidin-1- yl]imidazo[1,2-c]pyrimidin-7-yl}benzonitrile

488.2 TFA 133 4-[5-({(3R)-1-[(2R)-2- hydroxypropyl]piperidin-3-yl}methoxy)-8-(3-methyl-2-oxo-2,3- dihydro-1,3-benzoxazol-6-yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

539.2 TFA 134 4-[5-({(3R)-1-[(2S)-2- hydroxypropyl]piperidin-3-yl}methoxy)-8-(3-methyl-2-oxo-2,3- dihydro-1,3-benzoxazol-6-yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

539.2 TFA 135 4-[5-{[(3R)-1-(2-hydroxy-2- methylpropyl)piperidin-3-yl]methoxy}-8-(3-methyl-2-oxo-2,3- dihydro-1,3-benzoxazol-6-yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

553.2 TFA 136 4-[5-({(3R)-1-[(2R)-2- hydroxypropyl]piperidin-3-yl}methoxy)-8-(1-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

523.2 TFA 137 4-[5-({(3R)-1-[(2S)-2- hydroxypropyl]piperidin-3-yl}methoxy)-8-(1-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

523.2 TFA 138 4-[5-{[(3R)-1-(2-hydroxy-2- methylpropyl)piperidin-3-yl]methoxy}-8-(1-methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7- yl]benzonitrile

537.2 TFA

Example A: LSD1 Histone Demethylase Biochemical Assay

LANCE LSD1/KDM1A demethylase assay—10 μL of 1 nM LSD-1 enzyme (ENZOBML-SE544-0050) in the assay buffer (50 mM Tris, pH 7.5, 0.01% Tween-20,25 mM NaCl, 5 mM DTT) were preincubated for 1 hour at 25° C. with 0.8 μLcompound/DMSO dotted in black 384 well polystyrene plates. Reactionswere started by addition of 10 μL of assay buffer containing 0.4 μMBiotin-labeled Histone H3 peptide substrate:ART-K(Mel)-QTARKSTGGKAPRKQLA-GGK(Biotin) SEQ ID NO: 1 (AnaSpec 64355)and incubated for 1 hour at 25° C. Reactions were stopped by addition of10 μL 1×LANCE Detection Buffer (PerkinElmer CR97-100) supplemented with1.5 nM Eu-anti-unmodified H3K4 Antibody (PerkinElmer TRF0404), and 225nM LANCE Ultra Streptavidin (PerkinElmer TRF102) along with 0.9 mMTranylcypromine-HCl (Millipore 616431). After stopping the reactionsplates were incubated for 30 minutes and read on a PHERAstar FS platereader (BMG Labtech). IC₅₀ data for the example compounds is provided inTable 1 (the symbol “+” refers to IC₅₀≤50 nM; “++” refers to IC50>50 nMand ≤500 nM; “+++” refers to IC50>500 nM and ≤1000 nM).

TABLE 1 Example No. IC₅₀ (nM) 1 + 2 ++ 3 + 4 + 5 + 6 ++ 7 + 8 + 9 + 10 +11 ++ 12 ++ 13 + 14 + 15 ++ 16 ++ 17 + 18 ++ 19 + 20 + 21 ++ 22 ++ 23 ++24 + 25 ++ 26 ++ 27 + 28 + 29 + 30 + 31 + 32 + 33 + 34 + 35 + 36 + 37 +38 + 39 + 40 + 41 + 42 + 43 + 44 ++ 45 + 46 + 47 + 48 ++ 49 + 50 ++ 51 +52 + 53 + 54 + 55 + 56 + 57 + 58 + 59 + 60 + 61 ++ 62 + 63 + 64 + 65 +66 ++ 67 ++ 68 + 69 + 70 + 71 + 72 + 73 ++ 74 ++ 75 ++ 76 + 77 + 78 + 79++ 80 + 81 ++ 82 + 83 + 84 ++ 85 + 86 + 87 + 88 + 89 + 90 + 91 + 92 +93 + 94 + 95 + 96 + 97 + 98 + 99 + 100 + 101 + 102 + 103 + 104 + 105 +106 + 107 ++ 108 ++ 109 + 110 + 111 + 112 ++ 113 + 114 + 115 + 116 +117 + 118 ++ 119 ++ 120 + 121 + 122 + 123 + 124 + 125 + 126 ++ 127 +128 + 129 + 130 + 131 ++ 132 ++ 133 ++ 134 + 135 ++ 136 ++ 137 + 138 ++

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound which is4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile,or a pharmaceutically acceptable salt thereof.
 2. A compound which is4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile.3. A pharmaceutical composition comprising the compound of claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier or excipient.
 4. A pharmaceuticalcomposition comprising the compound of claim 2 and at least onepharmaceutically acceptable carrier or excipient.
 5. A compound which is4-[5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile,or a pharmaceutically acceptable salt thereof.
 6. A compound which is4-[5-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-8-(1-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile.7. A pharmaceutical composition comprising the compound of claim 5, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier or excipient.
 8. A pharmaceuticallycomposition comprising the compound of claim 6 and at least onepharmaceutically acceptable carrier or excipient.
 9. A compound which is4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile,or a pharmaceutically acceptable salt thereof.
 10. A compound which is4-[5-[4-(dimethylamino)piperidin-1-yl]-8-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-c]pyrimidin-7-yl]benzonitrile.11. A pharmaceutical composition comprising the compound of claim 9, apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier or excipient.
 12. A pharmaceuticalcomposition comprising the compound of claim 10 and at least onepharmaceutically acceptable carrier or excipient.